Sulfonamide compounds and uses thereof as medicines

ABSTRACT

The present invention relates to a sulfonamide compound of the formula (I): 
                 
 
wherein each symbol is as defined in the specification, a salt thereof, and a pharmaceutical composition containing same. This compound can be an effective agent for the prophylaxis and treatment of the diseases curable based on a hypoglycemic action, and the diseases curable based on a cGMP-PDE inhibitory action, a smooth muscle relaxing action, a bronchodilating action, a vasodilating action, a smooth muscle cell inhibitory action and an allergy suppressing action.

TECHNICAL FIELD

The present invention relates to novel sulfonamide compounds. Moreparticularly, the present invention relates to novel sulfonamidecompounds and salts thereof having hypoglycemic activity or PDE-Vinhibitory activity. The present invention also relates to a method forproducing the above-mentioned sulfonamide compound and salts thereof.Moreover, The present invention relates to pharmaceutical compositionscomprising the above-mentioned sulfonamide compound or a salt thereof asan active ingredient.

DISCLOSURE OF THE INVENTION

The present invention aims at providing novel sulfonamide compounds,pharmaceutically acceptable salts thereof and pharmaceuticalpreparations comprising the above-mentioned sulfonamide compound or apharmaceutically acceptable salt thereof as an active ingredient, whichare used as an agent for the prophylaxis and treatment of impairedglucose tolerance disorder, diabetes (e.g., type II diabetes),gestational diabetes, diabetic complications (e.g., diabetic gangrene,diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis,diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy,diabetic cataract, diabetic retinopathy and the like), insulinresistance syndrome (e.g., insulin receptor abnormality,Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome,Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly and thelike), polycystic ovary syndrome, hyperlipidemia, atherosclerosis,cardiovascular diseases (e.g., stenocardia, cardiac failure and thelike), hyperglycemia (e.g., those characterized by abnormalsaccharometabolism such as eating disorders), pancreatitis,osteoporosis, hyperuricemia, hypertension, inflammatory bowel diseases,and skin disorders related to an anomaly of differentiation of epidermiccells; and which, based on the cGMP-PDE (particularly PDE-V) inhibitoryaction, smooth muscle relaxing action, bronchodilating action,vasodilating action, smooth muscle cell inhibitory action, allergysuppressing action and the like, are used as prophylactic andtherapeutic agents for angina pectoris, hypertension, pulmonaryhypertension, congestive heart failure, glomerulopathy (e.g., diabeticglomerulosclerosis), tubulointerstitial disorders (e.g., kidney diseasesinduced by FK506, cyclosporin and the like), renal failure,atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty),peripheral vascular diseases, cerebral apoplexy, chronic reversibleobstructive impairment (e.g., bronchitis, asthma inclusive of chronicasthma and allergic asthma), autoimmune diseases, allergic rhinitis,urticaria, glaucoma, diseases characterized by impaired intestinalmotility (e.g., irritable bowel syndrome), impotence (e.g., organicimpotence, psychic impotence and the like), nephritis, cancer cachexia,restenosis after PTCA, cachexia (e.g., progressive weight loss due tolipolysis, myolysis, anemia, edema, anorexia and the like in chronicdiseases such as cancer, tuberculosis, endocrine diseases and AIDS), andthe like.

The sulfonamide compound, which is the novel compound of the presentinvention, is expressed by the formula (I):

wherein

-   R¹ is an aryl or heterocyclic group substituted by at least one    substituent selected from the group consisting of (1) aryl, (2) a    heterocyclic group optionally substituted by oxo or halogen, (3)    halogen, (4) halo(lower)alkyl, (5) lower alkoxy optionally    substituted by cyclo(lower)alkyl, (6) amino optionally substituted    by at least one substituent selected from the group consisting of    lower alkyl optionally substituted by cyclo(lower)alkyl, protected    carboxy, acyl, lower alkylcarbamoyl, and lower alkanesulfonyl, (7)    nitro and (8) lower alkynyl optionally substituted by aryl,-   R² is a lower alkyl or lower alkoxy,-   R³ is a hydrogen or lower alkyl,-   R⁴ is a lower alkenyl optionally substituted by aryl or heterocyclic    group, aryl optionally, substituted by carboxy or protected carboxy,    lower alkyl optionally substituted by acyloxy, amino optionally    substituted by lower alkyl, or heterocyclic group optionally    substituted by halogen, and-   A is a lower alkylene    [hereinafter to be also referred to as the objective compound (I)].

Preferred salts of the objective compound (I) are conventional saltsthat are non-toxic and acceptable for use as pharmaceuticals. Examplesthereof include salts with alkali metal such as sodium and potassium,salts with alkaline earth metal such as calcium and magnesium, saltswith inorganic base such as ammonium salt, salts with organic amine suchas triethylamine, pyridine, picoline, ethanolamine and triethanolamine,salts with inorganic acid such as hydrochloric acid, hydrobromic acid,sulfuric acid and phosphoric acid, salts with organic carboxylic acidsuch as formic acid, acetic acid, trifluoroacetic acid, maleic acid andtartaric acid, addition salts with sulfonic acid such as methanesulfonicacid, benzenesulfonic acid and p-toluenesulfonic acid, and salts or acidaddition salts with base such as basic or acidic amino acid such asarginine, aspartic acid and glutamic acid.

The objective compound (I) and a salt thereof of the present inventioncan be produced by the method shown by the following reaction formulas.

wherein each symbol in the formula is as defined above.

The objective compound (I) and a salt thereof of the present inventioncan be also produced by the method shown by the following reactionformulas.

wherein R^(4a) is aryl substituted by at least one protected carboxy,R^(4b) is aryl substituted by at least one carboxy, and other symbolsare as defined above.

wherein R^(1a) is aryl or heterocyclic group substituted by at least oneamino substituted by at least one protected carboxy, R^(1b) is aryl orheterocyclic group substituted by at least one unsubstituted ormonosubstituted amino, and other symbols are as defined above.

wherein R^(a) is hydrogen or lower alkyl optionally substituted bycyclo(lower)alkyl, R^(1c) is aryl or heterocyclic group substituted byat least one amino substituted by at least one lower alkyl optionallysubstituted by cyclo(lower)alkyl, and other symbols are as definedabove.

wherein R^(1d) is aryl or heterocyclic group substituted by at least onehalogen, R^(b) and R^(c) are each independently hydrogen, lower alkyloptionally substituted by cyclo(lower)alkyl, protected carboxy, acyl orlower alkanesulfonyl, R^(1e) is aryl or heterocyclic group substitutedby at least one amino optionally substituted by at least one substituentselected from the group consisting of lower alkyl optionally substitutedby cyclo(lower)alkyl, protected carboxy, acyl and lower alkanesulfonyl,and other symbols are as defined above.

wherein R^(1f) is aryl or heterocyclic group substituted by at least oneamino substituted by at least one acyl, and other symbols are as definedabove.

wherein each symbol in the formula is as defined above.

wherein R^(1g) is aryl or heterocyclic group substituted by at least oneamino substituted by at least one lower alkanesulfonyl, and othersymbols are as defined above.

Various definitions included in the entire specification are explainedin detail in the following.

“Lower” means 1 to 6 carbon atoms, unless otherwise specified.

“Alkyl” and “alkyl moiety” are preferably linear or branched alkyl.Specific examples include methyl, ethyl, 1-propyl, isopropyl, 1-butyl,i-butyl, t-butyl, sec-butyl, 1-pentyl, i-pentyl, sec-pentyl, t-pentyl,methylbutyl, 1,1-dimethylpropyl, 1-hexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl,2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 1-ethyl-1-methylpropyl, 1-heptyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 4-ethylpentyl,1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl,4,4-dimethylpentyl, 1-propylbutyl, 1-octyl, 1-methylheptyl,2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl,5-ethylhexyl, 1,1-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl,4,4-dimethylhexyl, 5,5-dimethylhexyl, 1-propylpentyl, 2-propylpentyl andthe like.

Of these, particularly preferred is alkyl having 1 to 6 carbon atoms.

“Alkenyl” and “alkenyl moiety” are preferably exemplified by linear orbranched alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl and the like.

Of these, preferred is alkenyl having 2 to 6 carbon atoms, which is morepreferably ethenyl.

“Cyclo(lower)alkyl” is cycloalkyl having 3 to 10, preferably 3 to 7,carbon atoms. Preferable examples thereof include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, with morepreference given to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Examples of preferable lower alkylene include methylene, ethylene,propylene, butylene, pentylene, hexylene and the like, with particularpreference given to alkylene having up to 4 carbon atoms. Of these,particularly preferred is methylene.

Examples of preferable lower alkynyl include linear or branched alkynyl,such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,2-methyl-3-butynyl, 1,1-dimethyl-2-butynyl, 1-hexynyl, 5-hexynyl and thelike.

Of these, particularly preferred is alkynyl having 2 to 6 carbon atoms,which is more preferably ethynyl.

Lower alkoxy is linear or branched alkyloxy having up to 6 carbon atoms.Prefererable examples thereof include methoxy, ethoxy, 1-propyloxy,i-propyloxy, 1-butyloxy, i-butyloxy, sec-butyloxy, t-butyloxy,1-pentyloxy, i-pentyloxy, sec-pentyloxy, t-pentyloxy, 2-methylbutoxy,1-hexyloxy, i-hexyloxy, t-hexyloxy, sec-hexyloxy, 2-methylpentyloxy,3-methylpentyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy,1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy,1-ethyl-1-methylpropyloxy, and the like.

More preferred is alkoxy having up to 5 carbon atoms, such as methoxy,ethoxy, 1-propyloxy, i-propyloxy, 1-butyloxy, i-butyloxy, sec-butyloxy,t-butyloxy, 1-pentyloxy and the like.

“Lower alkanesulfonyl” is sulfonyl substituted by the above-definedlower alkyl. Preferred is lower alkanesulfonyl having up to 4 carbonatoms, more preferably 1-butanesulfonyl.

Halogen is exemplified by fluorine atom, chlorine atom, bromine atom andiodine atom.

“Halo(lower)alkyl” is a linear or branched alkyl having up to 6 carbonatoms, which is substituted by fluorine atom, chlorine atom, bromineatom or iodine atom, and is preferably a linear or branched alkyl havingup to 6 carbon atoms, which is substituted by fluorine atom, chlorineatom or bromine atom. Examples thereof include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl,1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 2-fluoroethyl,2-chloroethyl, 2-bromoethyl, 1,2-difluoroethyl, 1,2-dichloroethyl,1,2-dibromo-ethyl, 2,2,2-trifluoroethyl, heptafluoroethyl,1-fluoropropyl, 1-chloropropyl, 1-bromopropyl, 2-fluoropropyl,2-chloropropyl, 2-bromopropyl, 3-fluoropropyl, 3-chloropropyl,3-bromopropyl, 1,2-difluoropropyl, 1,2-dichloropropyl,1,2-dibromopropyl, 2,3-difluoropropyl, 2,3-dichloropropyl,2,3-dibromopropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl,2-fluorobutyl, 2-chlorobutyl, 2-bromobutyl, 4-fluorobutyl,4-chlorobutyl, 4-bromobutyl, 4,4,4-trifluorobutyl,2,2,3,3,4,4,4-heptafluorobutyl, perfluorobutyl, 2-fluoropentyl,2-chloropentyl, 2-bromopentyl, 5-fluoropentyl, 5-chloropentyl,5-bromopentyl, perfluoropentyl, 2-fluorohexyl, 2-chlorohexyl,2-bromohexyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, perfluorohexyland the like.

Preferable alkyl of the “lower alkylcarbamoyl” is the above-mentionedlower alkyl.

In the present specification, aryl means unsubstituted aryl oralkyl-substituted aryl. Examples of preferable unsubstituted arylinclude C₆-C₁₀ aryl, such as phenyl, naphthyl and pentalenyl. Of these,preferred is phenyl and naphthyl.

“Alkyl-substituted aryl” means aryl substituted by at least one alkyl.The number of alkyl substituents is preferably 1 to 4. The aryl moietyof “alkyl-substituted aryl” is the same as for the aforementionedunsubstituted aryl, and the “alkyl moiety” is as defined above, which ispreferably lower alkyl. Specific examples of preferablealkyl-substituted aryl include tolyl, xylyl, mesityl, ethylphenyl,propylphenyl and the like, with more preference given to p-tolyl.

“Heterocyclic group” is a saturated or unsaturated, heteromonocyclic orheteropolycyclic group having at least one hetero atom, such as oxygenatom, sulfur atom, nitrogen atom and selenium atom. Particularly,unsaturated heteromonocyclic group is preferable. More preferred are theheterocyclic groups described in the below-mentioned (1), (2), (4), (7)and (9), which are still preferably pyridyl, pyrrolyl, pyrrolidinyl,oxazolidinyl, thienyl and furyl.

Heteromonocyclic group includes the following.

(1) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered)heteromonocyclic group having 1 to 4 nitrogen atoms, such as pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl and 2H-1,2,3-triazolyl), tetrazolyl (e.g.,1H-tetrazolyl and 2H-tetrazolyl) and the like.(2) Saturated 3 to 8-membered (more preferably 5- or 6-membered)heteromonocyclic group having 1 to 4 nitrogen atoms, such aspyrrolidinyl, imidazolidinyl, piperidyl, pyperazinyl and the like.(3) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered)heteromonocyclic group having 1 or 2 oxygen atoms and 1 to 3 nitrogenatoms, such as oxazolyl, isoxazolyl, oxadiazolyl (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,5-oxadiazolyl) and thelike.(4) Saturated 3 to 8-membered (more preferably 5- or 6-membered)heteromonocyclic group having 1 or 2 oxygen atoms and 1 to 3 nitrogenatoms, such as oxazolidinyl, thiazolidinyl, morpholinyl, sydnonyl andthe like.(5) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered)heteromonocyclic group having 1 or 2 sulfur atoms and 1 to 3 nitrogenatoms, such as thiazolyl, isothiazolyl, thiadiazolyl (e.g.,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl and1,2,5-thiadiazolyl), dihydrothiazinyl and the like.(6) Saturated 3 to 8-membered (more preferably 5- or 6-membered)heteromonocyclic group having 1 or 2 sulfur atoms and 1 to 3 nitrogenatoms, such as thiazolidinyl and the like.(7) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered)heteromonocyclic group having 1 or 2 sulfur atoms, such as thienyl,dihydrodithinyl, dihydrodithionyl and the like.(8) Saturated 3 to 8-membered (more preferably 5- or 6-membered)heteromonocyclic group having 1 or 2 oxygen atoms, such astetrahydrofuryl, tetrahydropyranyl and the like.(9) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered)heteromonocyclic group having one oxygen atom, such as furyl and thelike.(10) Spiroheterocyclic group having 1 or 2 oxygen atoms, such asdioxaspiroundecanyl (e.g., 1,5-dioxaspiro[5,5]undecanyl) and the like.(11) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered)heteromonocyclic group having one oxygen atom and 1 or 2 sulfur atoms,such as dihydroxathinyl.

Examples of heteropolycyclic group include the following.

(12) Saturated or unsaturated 7 to 12-membered (more preferably 8 to10-membered) heteropolycyclic (more preferably heterodicyclic) grouphaving 1 to 4 nitrogen atoms.

Specific examples thereof include benzimidazolyl, indolyl,2,3-dihydrobenzimidazolyl, pyrazolopyrimidinyl (e.g.,pyrazolo[1,5-a]pyrimidinyl), tetrahydropyrazolopyrimidinyl (e.g.,4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl), imidazopyrazolyl (e.g.,4H-imidazo[1,2-b]pyrazolyl), dihydroimidazopyrazolyl (e.g.,2,3-dihydroimidazo[1,2-b]pyrazolyl), imidazopyridyl (e.g.,imidazo[1,5-a] (or [1,2-a] or [3,4-a])pyridyl, 1H (or 3H)-imidazo[4,5-b](or [4,5-c])pyridyl), pyrrolopyridyl (e.g., 1H-pyrrolo[3,2-b]pyridyl),pyrazolopyridyl (e.g., pyrazolo[1,5-a] (or [2,3-a])pyridyl, 1H (or2H)-pyrazolo[4,3-b]pyridyl), benzo-pyrazolyl (e.g., 1H (or2H)-benzo[c]pyrazolyl), dihydrobenz-imidazolyl, benzotriazolyl (e.g.,benzo[d][1H-1,2,3]triazolyl), indolidinyl, isoindolyl (e.g.,1H-isoindolyl), indazolyl (e.g., 1H (or 2H or 3H)-indazolyl), indolinyl,isoindolinyl, purinyl, quinolidinyl (e.g., 4H-quinolidinyl),isoquinolyl, quinolyl, phthaladinyl, naphthalidinyl (e.g.,1,8-naphthalidinyl), quinoxalinyl, dihydroquinoxalinyl (e.g.,1,2-dihydroquinoxalinyl), tetrahydroquinoxalinyl (e.g.,1,2,3,4-tetrahydroquinoxalinyl), quinazolinyl, dihydroquinazolinyl(e.g., 1,4 (or 3,4)-dihydroquinazolinyl), tetrahydroquinazolinyl (e.g.,1,2,3,4-tetrahydroquinazolinyl), cinnolinyl, pteridinyl,pyrazinopyridazinyl (e.g., pyrazino[2,3-d]pyridazinyl), imidazotriazinyl(e.g., imidazo[1,2-b][1,2,4]triazinyl, imidazopyrazinyl (e.g.,1H-imidazo[4,5-b]pyrazinyl), imidazopyrimidine (e.g., 3H-purine andimidazo[1,5-a] (or [3,4-a])pyrimidine), imidazopyridazinyl (e.g.,imidazo[2,3-b] (or [3,4-b])pyridazinyl), 1H-1(or 2)-pyrinedinyl and thelike.

(13) Saturated or unsaturated 7 to 12-membered (more preferably 8 to10-membered) heteropolycyclic (more preferably heterodicyclic) grouphaving 1 to 3 oxygen atoms.

Specific examples thereof include benzofuranyl (e.g., benzo[b] (or[c])furanyl), isobenzofuranyl, furopyridyl, chromenyl (e.g.,2H-chromenyl), chromanyl, isochromanyl, benzoxepinyl (e.g.,3-benzoxepinyl), cyclopentapyranyl (e.g., cyclopenta[b]pyranyl),furopyranyl (e.g., 2H-furo[3,2-b]pyranyl, and the like.

(14) Saturated or unsaturated 7 to 12-membered (more preferably 8 to10-membered) heteropolycyclic (more preferably heterodicyclic) grouphaving 1 to 3 sulfur atoms.

Specific examples thereof include benzothiophenyl (e.g.,benzo[b]thiophenyl), dihydrodithianaphthalenyl (e.g.,4H-1,3-dithianaphthalenyl), dithianaphthalenyl (e.g.,1,4-dithianaphthalenyl) and the like.

(15) Saturated or unsaturated 7 to 12-membered (more preferably 8 to10-membered) heteropolycyclic (more preferably heterodicyclic) grouphaving 1 to 3 nitrogen atoms and 1 or 2 oxygen atoms.

Specific examples thereof include dioxoloimidazolyl (e.g.,4H-1,3-dioxolo[4,5-d]imidazolyl, benzoxazinyl (e.g.,4H-3,1-benzoxazinyl), pyridoxazinyl (e.g., 5H-pyrid[2,3-d]oxazinyl),pyrazolooxazolyl (e.g., 1H-pyrazolo[4,3-d]oxazolyl), furopyridyl, andthe like.

(16) Saturated or unsaturated 7 to 12-membered (more preferably 8 to10-membered) heteropolycyclic (more preferably heterodicyclic) grouphaving 1 to 3 nitrogen atoms and 1 or 2 sulfur atoms.

Specific examples thereof include thienoimidazolyl (e.g.,thieno[2,3-d]imidazolyl), thienopyridyl, dithiadiazaindanyl (e.g.,2,3-dithia-1,5-diazaindanyl) and the like.

(17) Saturated or unsaturated 7 to 12-membered (more preferably 8 to10-membered) heteropolycyclic (more preferably heterodicyclic) grouphaving 1 to 3 oxygen atoms and 1 or 2 sulfur atoms.

Specific examples thereof include thienofuranyl (e.g.,thieno[2,3-b]furanyl), and the like.

(18) Saturated or unsaturated 7 to 12-membered (more preferably 8 to10-membered) heteropolycyclic (more preferably heterodicyclic) grouphaving 1 nitrogen atom, 1 oxygen atom and 1 sulfur atom.

Specific examples thereof include oxathiolopyrrolyl (e.g.,4H[1,3]-oxathiolo[5,4-b]pyrrolyl, and the like.

(19) Saturated or unsaturated 7 to 12-membered (more preferably 8 to10-membered) heteropolycyclic (more preferably heterodicyclic) grouphaving 1 or 2 selenium atoms.

Preferred specific examples include benzoselenophenyl (e.g., benzo[b](or [c])selenophenyl), and the like.

(20) Saturated or unsaturated 7 to 12-membered (more preferably 8 to10-membered) heteropolycyclic (more preferably heterodicyclic) grouphaving 1 or 2 selenium atoms and 1 to 3 nitrogen atoms.

Specific examples thereof include selenopyridyl (e.g.,seleno[3,2-b]pyridyl), and the like.

“Acyl” and “acyl moiety” are exemplified by carbamoyl, aliphatic acyl,and acyl having heterocyclic group called to as aromatic acyl or acylhaving heterocyclic group called to as heterocyclic acyl. Preferableexamples of the above-mentioned acyl include carbamoyl; aliphatic acylsuch as lower alkanoyl having 1 to 10, preferably 1 to 6, carbon atoms,(e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, 3,3-dimethylbutanoyl,heptanoyl, octanoyl, nonanoyl, decanoyl and the like), alkoxycarbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl,t-pentyloxycarbonyl, heptyloxycarbonyl and the like), butyloxycarbonyl,alkanesulfonyl (e.g., methanesulfonyl, ethanesulfonyl and the like), andalkoxysulfonyl (e.g., methoxysulfonyl and ethoxysulfonyl); aromatic acylsuch as aroyl (e.g., benzoyl, toluoyl, naphthoyl and the like),aryl(lower)alkanoyl (e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl,phenylpropanoyl, phenylbutanoyl, phenylisobutyryl, phenylpentanoyl andphenylhexanoyl) and naphthyl(lower)alkanoyl (e.g., naphthylacetyl,naphthylpropanoyl and naphthylbutanoyl)), aryl(lower)alkenoyl (e.g.,phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl,phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl) andnaphthyl(lower)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl andnaphthylpentenoyl)), aryl(lower)alkoxycarbonyl (e.g.,phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl)), aryloxycarbonyl(e.g., phenoxycarbonyl, naphthyloxycarbonyl and the like),aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxy-propionyl and thelike), arylcarbamoyl (e.g., phenylcarbamoyl and the like),arylthiocarbamoyl (e.g., phenylthiocarbamoyl and the like), andarylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl and thelike); heterocyclic acyl such as arenesulfonyl (e.g., benzenesulfonyland p-toluenesulfonyl), heterocyclecarbonyl; heterocycle(lower)alkanoyl(e.g., thienylacetyl, thienyl-propanoyl, thienylbutanoyl,thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, tetrazolylacetyl andthe like), heterocycle(lower)alkenoyl (e.g., heterocyclepropenoyl,heterocyclebutenoyl, heterocyclepentenoyl, heterocyclehexenoyl and thelike), and heterocycleglyoxyloyl (e.g., thiazolylglyoxyloyl,thienyl-glyoxyloyl and the like); and the like.

More specifically, the preferable heterocycle moiety of theabove-mentioned “heterocyclecarbonyl”, “heterocycle(lower)alkanoyl”,“heterocycle(lower)alkenoyl” and “heterocycleglyoxyloyl” means asaturated or unsaturated heteromonocyclic or heteropolycyclic grouphaving at least one hetero atom such as oxygen atom, sulfur atom,nitrogen atom and the like, with particular preference given to theheterocyclic groups mentioned above.

The aforementioned acyl moiety may have 1 to 10 same or differentsuitable substituent(s), such as halogen (e.g., fluorine, chlorine,bromine and iodine), hydroxy, nitro, lower alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl), amino,protected amino, heterocycle-(lower)alkylamino having theabove-mentioned heterocycle moiety and lower alkyl moiety, lower alkoxy(e.g., methoxy, ethoxy, propoxy, butyloxy, t-butyloxy, pentyloxy andhexyloxy), carboxy, protected carboxy,N,N-di(lower)alkylamino(lower)alkyl (e.g., N,N-dimethylaminomethyl,N,N-diethylaminomethyl, N,N-dipropylaminomethyl, N,N-dimethylaminoethyl,N,N-diethylaminoethyl, N,N-dipropylaminoethyl, N,N-dimethylaminopropyl,N,N-diethylaminopropyl, N,N-dipropylaminopropyl, N,N-dibutylaminomethyl,N,N-dipentylaminomethyl and N,N-dihexylaminomethyl),hydroxyimino(lower)alkyl (e.g., hydroxyiminomethyl, hydroxyiminoethyl,hydroxyiminopropyl, hydroxyiminobutyl, hydroxyiminopentyl andhydroxyiminohexyl), arylimino(lower)alkyl exemplified byphenylimino(lower)alkyl (e.g., phenyliminomethyl, phenyliminoethyl,phenyliminopropyl, phenyliminobutyl, phenyliminopentyl andphenyliminohexyl), acyl such as lower alkanoyl (e.g., formyl, acetyl,propanoyl, butanoyl, pentanoyl and hexanoyl),hydroxy(lower)alkylheterocycle(lower)alkyl having the above-mentionedlower alkyl moiety and heterocycle moiety, mono- (or di- ortri-)halo(lower)alkyl, and arylamino (e.g., phenylamino).

More preferable “acyl” is the above-mentioned lower alkanoyl.

The preferable acyl moiety of acyloxy is exemplified by acyl moietydefined above, more preferably acetyl.

Preferable example of the protected carboxy is esterified carboxy.

Examples of preferable ester moiety of the esterified carboxy includelower alkyl esters such as methyl ester, ethyl ester, propyl ester,isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentylester and hexyl ester, and the like. These groups may have at least oneappropriate substituent, which is exemplified by loweralkanoyloxy(lower)alkyl ester such as acetoxymethyl ester,propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethylester, pivaloyloxymethyl ester, hexanoyloxy-methyl ester, 1 (or2)-acetoxyethyl ester, 1 (or 2 or 3)-acetoxypropyl ester, 1 (or 2, 3 or4)-acetoxybutyl ester, 1 (or 2)-propionyloxyethyl ester, 1 (or 2 or3)-propionyloxypropyl ester, 1 (or 2)-butyryloxyethyl ester, 1 (or2)-isobutyryloxyethyl ester, 1 (or 2)-pivaloyloxyethyl ester, 1 (or2)-hexanoyl-oxyethyl ester, isobutyryloxymethyl ester,2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1 (or2)-pentanoyloxyethyl ester), lower alkanesulfonyl-(lower)alkyl ester(e.g., 2-mesylethyl ester), mono- (or di- or tri-)-halo(lower)alkylester (e.g., 2-iodoethyl ester and 2,2,2-trichloroethyl ester), loweralkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethylester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester,1-ethoxycarbonyloxyethyl ester and 1-isopropoxycarbonyloxyethyl ester),phthalidylidene-(lower)alkyl ester and (5-loweralkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester (e.g.,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester and(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester); lower alkenyl ester (e.g.,vinyl ester and allyl ester); lower alkynyl ester (e.g., ethynyl esterand propynyl ester); aryl(lower)alkyl ester optionally having at leastone suitable substituent, such as mono- (or di- ortri-)phenyl(lower)alkyl ester optionally having at least one suitablesubstituent, which is exemplified by benzyl ester, 4-methoxybenzylester, 4-nitrobenzyl ester, phenylethyl ester, trityl ester, benzhydrylester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester and4-hydroxy-3,5-di-t-butylbenzyl ester; aryl ester optionally having atleast one suitable substituent, such as phenyl ester, 4-chlorophenylester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester andcumenyl ester; cyclo(lower)alkyl ester (e.g., cyclohexyl ester);phthalidyl ester; and the like.

When the above-mentioned substituents are substituted, the number of thesubstituents is preferably 1 to 4, unless particularly specified.

Preferable examples of the objective compound (I) are the compound ofthe formula (I) wherein R¹ is pyridyl optionally substituted by at leastone substituent selected from the group consisting of (1) aryl, (2) aheterocyclic group, (3) halogen, (4) halo(lower)alkyl, (5)lower alkoxyoptionally substituted by cyclo(lower)alkyl, (6) amino optionallysubstituted by at least one substituent selected from the groupconsisting of lower alkyl optionally substituted by cyclo(lower)alkyl,and protected carboxy, acyl and lower alkanesulfonyl, (7) nitro, and (8)lower alkynyl optionally substituted by aryl, and a salt thereof.

Of the objective compounds, another particularly preferable compound hasthe following formula (IA):

wherein

-   R² is lower alkyl or lower alkoxy,-   R³ is hydrogen or lower alkyl,-   R⁴ is lower alkenyl optionally substituted by aryl or heterocyclic    group, aryl optionally substituted by carboxy or protected carboxy,    lower alkyl optionally substituted by acyloxy, amino optionally    substituted by lower alkyl, or heterocyclic group optionally    substituted by halogen,-   R⁵ is pyrrolyl, furyl, or amino substituted by protected carboxy    optionally substituted by lower alkyl, and-   X is halogen,    and a salt thereof.

Particularly preferable groups are as follows.

-   R¹: 3-chloro-4-biphenylyl, 2-chloro-4-methoxyphenyl,    2-chloro-4-ethoxyphenyl, 2-chloro-4-(1-propoxy)phenyl,    2-chloro-4-isopropoxyphenyl, 2-chloro-4-(1-butoxy)phenyl,    2-chloro-4-(1-pentyloxy)phenyl,    2-chloro-4-((cyclopentylmethyl)oxy)phenyl, 2-chloro-4-ethoxyphenyl,    2-chloro-4-(N-(tert-butoxycarbonyl)-N-methylamino)phenyl,    2-chloro-4-(methylamino)phenyl, 2-chloro-4-(ethylmethylamino)phenyl,    2-chloro-4-(methyl-(1-propyl)amino)-phenyl,    4-(1-butyl)methylamino-2-chlorophenyl,    2-chloro-4-(dimethylamino)phenyl,    2-chloro-4-(ethylmethylamino)phenyl,    2-chloro-4-((1-butyl)methylamino)phenyl,    2-chloro-4-(methyl-(1-pentyl)amino)phenyl,    2-chloro-4-(N-(cyclohexylmethyl)-methylamino)phenyl,    4-bromo-2-chlorophenyl, 3-chloro-5-(trifluoromethyl)-2-pyridyl,    2-chloro-4-(2-furyl)phenyl,    2-chloro-4-(N-(ethoxycarbonyl)-N-methylamino)phenyl,    2-chloro-4-(N-(tert-butoxycarbonyl)-N-ethylamino)phenyl,    2-chloro-4-(N-(pivaloyl)-N-methylamino)phenyl,    2-chloro-4-(ethylamino)phenyl, 2-chloro-4-(diethylamino)phenyl,    2-chloro-4-(1-pentylethylamino)-phenyl, 2,6-dichloro-3-pyridyl,    2-chloro-4-(cyclohexylmethyloxy)-phenyl,    2-chloro-4-(1-pyrrolyl)phenyl, (2,4-dichloro-5-nitro)-phenyl,    (2,4-dichloro-5-(N,N-dimethylamino))phenyl,    (4-(N-(1-butanesulfonyl)-N-methylamino)-2-chlorophenyl,    2-chloro-4-(N-methyl-N-(1-propoxycarbonyl)amino)phenyl,    2-chloro-4-(N-methyl-N-(isopropoxycarbonyl)amino)phenyl,    4-(N-(tert-butoxycarbonyl)-amino)-2-chlorophenyl,    2-chloro-4-(ethoxycarbonylamino)phenyl,    2-chloro-4-(N-valerylamino)phenyl,    4-(N-(1-butanesulfonyl)amino)-2-chlorophenyl,    2-chloro-4-(N-(t-butylacetyl)amino)phenyl,-   R²: methyl, ethyl, ethoxy,-   R³: hydrogen, methyl,-   R⁴: (E)-2-(4-pyridyl)vinyl, 1-pentyl, 1-butyl, 4-methylphenyl,    1-propylamino, 1-butylamino, (E)-2-(phenyl)vinyl, 5-bromo-2-thienyl,    5-chloro-2-thienyl, 4-ethoxycarbonylphenyl, 4-carboxyphenyl,    4-acetoxybutyl,-   R⁵: N-(tert-butoxycarbonyl)-N-methylamino, 2-furyl,    N-(ethoxycarbonyl)-N-methylamino,    N-(tert-butoxycarbonyl)-N-ethylamino, 1-pyrrolyl,    N-methyl-N-(isopropoxycarbonyl)amino,    N-methyl-N-(isopropoxycarbonyl)amino, N-(tert-butoxycarbonyl)amino,    ethoxycarbonylamino,-   A: methylene,-   X: chlorine.

Preferable objective compounds (I) are as follows.

-   3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(E)-[2-(4-pyridyl)ethene]sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   5-[(4-acetoxybutane)sulfonylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(4-ethoxycarbonylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(4-carboxybenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-methoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-methoxybenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-ethoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-ethoxybenzyl)-2-methyl-5-((1-propylaminosulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-((1-butylaminosulfonyl)carbamoyl)-3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-propoxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-propoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-isopropoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-isopropoxybenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-5-((E)-(2-phenylethene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-5-[(5-chlorothiophen-2-yl)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   5-((1-propylaminosulfonyl)carbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   5-((1-butylaminosulfonyl)carbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-((cyclopentylmethyl)oxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-((cyclopentylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-ethoxybenzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-ethoxybenzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-[2-chloro-4-(1-propoxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine,-   3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(ethylmethylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(methyl-(1-propyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-((1-butyl)methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(dimethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(ethylmethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(methyl-(1-propyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-((1-butyl)methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(methyl-(1-pentyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl)-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(ethylmethylamino)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-phenylbenzyl)-2-ethoxy-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(1-propylaminosulfonyl)carbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(methyl(pivaloyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(ethoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(ethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(N,N-diethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(N-ethyl-N-(1-pentyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(methylamino)benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(N-methyl-N-propylamino)benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[2-chloro-4-(cyclohexylmethyloxy)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine    sodium salt,-   3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-5-(1-butanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2,4-dichloro-5-nitrobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2,4-dichloro-5-nitrobenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-[2,4-dichloro-5-(N,N-dimethylamino)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[2,4-dichloro-5-(N,N-dimethylamino)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(1-butanesulfonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine    sodium salt,-   3-(2-chloro-4-(N-methyl-N-(1-propoxycarbonyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(N-methyl-N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(ethoxycarbonylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(N-valerylamino)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(1-butanesulfonyl)amino)-2-chlorobenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(N-(t-butylacetyl)amino)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(4-amino-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(1-propoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(isopropoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   5-(1-butanesulfonylcarbamoyl)-3-(4-(N-t-butoxycarbonylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(4-amino-2-chlorobenzyl)-5-(1-butanesulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine,-   3-(4-ethoxycarbonylamino-2-chlorobenzyl)-2-methyl-5-(1-butanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-t-butoxycarbonylamino)-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-amino-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-ethoxycarbonylamino-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(3-(1-propyl)ureido)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-(4-(1-methyl-3-(1-propyl)ureido)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(2-oxo-1-pyrrolidinyl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,    3-(2-chloro-4-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(((2-(4-methylbenzene)sulfonylcarbamoyloxy)-ethyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-((6-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-5-((4-methylbenzenesulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-5-(((E)-2-phenylethenesulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(2-chloro-6-phenylpyridin-3-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(2-chloro-6-phenylpyridin-3-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)    methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-[(3-chloro-5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(3-chloro-5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(3-chloro-5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,-   3-[(5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-[(5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,-   3-(2-chloro-4-(phenylethynyl)benzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine    sodium salt,-   3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine    sodium salt,-   3-(2-chloro-4-(phenylethynyl)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine    sodium salt,-   5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine    sodium salt,-   3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine    sodium salt,-   3-(4-(N-(ethoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,    and-   3-(4-(N-(benzyloxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine.

The production methods of the objective compound (I) are explained indetail in the following.

Production Method 1:

The objective compound (I) and a salt thereof can be produced byreacting compound (II) or reactive derivative at carboxy thereof or asalt thereof with compound (III) or a salt thereof.

Preferable salts of compound (II), reactive derivative at carboxythereof and compound (III) are exemplified by those shown with regard tocompound (I).

Preferable reactive derivative at carboxy of compound (II) indludes acidhalide, acid anhydride inclusive of intramolecular acid anhydride,intermolecular acid anhydride and mixed acid anhydride, active amide,active ester and the like. Preferable examples thereof include acidchloride, acid azide, mixed acid anhydride with acid such as substitutedphosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid,diphenylphosphoric acid, dibenzylphosphoric acid and halogenatedphosphoric acid), dialklphosphinic acid, sulfurous acid, thiosulfuricacid, sulfuric acid, sulfonic acid (e.g., methanesulfonic acid),aliphatic carboxylic acid (e.g., acetic acid, propionic acid, butyricacid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid and trichloroacetic acid), aromatic carboxylic acid(e.g., benzoic acid), and the like; symmetric acid anhydride; activeamide with imidazole, 4-substituted imidazole, dimethylpyrazole,triazole or tetrazole; active ester (e.g., cyanomethyl ester,methoxymethyl ester, dimethyliminomethyl [(CH₃)₂N⁺═CH—] ester, vinylester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester,phenylazophenyl ester, phenylthio ester, p-nitrophenylthio ester,p-cresylthio ester, carboxymethylthio ester, pyranyl ester, pyridylester, piperidyl ester and 8-quinolylthio ester); esters with N-hydroxycompound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-1H-pyridone,N-hydroxysuccinimide and 1-hydroxy-1H-benzotriazole); and the like.These reactive derivatives can be appropriately selected according tothe kind of compound (II) to be used.

The reaction generally proceeds in a conventional solvent such as water,alcohol (e.g., methanol and ethanol), acetone, dioxane, acetonitrile,chloroform, methylene chloride, ethylene chloride, tetrahydrofuran,ethyl acetate, N,N-dimethylformamide, pyridine and a mixture thereof, orin any other solvent which does not adversely affect the reaction. Theseconventional solvents may be used alone or in combination.

When compound (II) is used in the form of a free acid or a salt thereofin this reaction, the reaction is preferably carried out in the presenceof a conventional condensing agent such asN,N′-dicyclohexylcarbodiimide,N-cyclohexyl-N′-morpholinoethylcarbodiimide,N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide,N,N′-diethylcarbodiimide, N,N′-diisopropylcarbodiimide,N-ethyl-N′-(3-dimethylamino-propyl)carbodiimide,N,N′-carbonylbis(2-methyl-imidazole),pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, ethoxyacetylene,1-alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphorate,isopropyl polyphosphate, phosphorous oxychloride (phosphoryl chloride),phosphorus trichloride, diphenylphosphoryl azide, diphenylchlorophosphate, diphenylphosphinic chloride, thionyl chloride, oxalylchloride, lower alkyl haloformate (e.g., ethyl chloroformate andisopropyl chloroformate), triphenylphosphine,2-ethyl-7-hydroxybenzisoxazolium salt, intramolecular salt of2-ethyl-5-(m-sulfophenyl)-isoxazolium hydroxide,1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, and so-calledVilsmeier reagent (prepared by the reaction of N,N-dimethylformamidewith thionyl chloride, phosgene, trichloromethyl chloroformate,phosphorous oxychloride, or the like), and the like.

The reaction can be carried out in the presence of an inorganic ororganic base such as alkali metal bicarbonate, tri(lower)alkylamine,pyridine, 4-dimethylaminopyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylaniline (e.g., N,N-dimethylaniline),N,N-di(lower)alkylbenzylamine, and the like.

The reaction temperature is not particularly limited, and the reactionis generally carried out under cooling to heating.

Production Method 2:

The objective compound (I-b) and a salt thereof can be produced bysubjecting compound (I-a) or a salt thereof to elimination ofcarboxy-protecting group.

The preferable salts of compound (I-a) and (I-b) are exemplified bythose shown with regard to compound (I).

This reaction is carried out according to a conventional method such ashydrolysis and the like.

Hydrolysis is preferably carried out in the presence of a base or anacid inclusive of Lewis acid. Examples of preferable base includeinorganic base and organic base such as alkali metal (e.g., lithium,sodium, potassium and the like), alkaline earth metal (magnesium,calcium and the like), and hydroxide, carbonate and bicarbonate thereof,trialkylamine (e.g., trimethylamine, triethylamine and the like),picoline, 1,5-diazabicyclo-[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene andthe like. Preferable acid includes organic acid (e.g., formic acid,acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acidand the like), inorganic acid (e.g., hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid and the like) and Lewis acid (borontribromide and the like).

The reaction generally proceeds in a solvent such as water, alcohol(e.g., methanol, ethanol and the like), xylene, diethyleneglycolmonomethyl ether, methylene chloride, tetrahydrofuran, mixtures thereofand the like, or any other solvent that does not adversely affect thereaction. A liquid base or acid can be also used as a solvent. Thereaction temperature is not particularly limited and the reactiongenerally proceeds under cooling to heating.

Production Method 3:

Compound (I-d) and a salt thereof can be produced by subjecting compound(I-c) or a salt thereof to elimination of amino-protecting group.

The preferable salts of compound (I-c) and (I-d) are exemplified bythose shown with regard to compound (I).

This reaction can be carried out in essentially the same manner as inProduction Method 2, and therefore, the method of reaction and reactionconditions (e.g., solvent, reaction temperature and the like) are to bereferred to those disclosed for Production Method 2.

Production Method 4:

The objective compound (I-e) and a salt thereof can be prepared byadding compound (IV) to compound (I-d) or a salt thereof by reduction.

The preferable salts of compound (I-d) and (I-e) are exemplified bythose shown with regard to compound (I).

The reduction can be carried out in chemical reduction and catalyticreduction, which may be carried out by a conventional method.

The preferable reducing agent used in the chemical reduction is, forexample, metal such as tin, zinc and iron, a combination of such a metaland/or a metal compound such as chromium chloride and chromium acetate,and an organic acid or inorganic acid such as formic acid, acetic acid,propionic acid, trifluoroacetic acid, p-toluenesulfonic acid,hydrochloric acid and hydrobromic acid, a combination of theaforementioned metal and/or metal compound and a base (e.g., ammonia,ammonium chloride, sodium hydroxide and the like), metal hydridecompound such as aluminum hydride compound (e.g., lithium aluminumhydride, alminium sodium hydride, aluminum hydride, trimethoxy aluminumlithium hydride, tri-t-butoxy aluminum hydride and the like),borohydride compound (e.g., sodium borohydride, lithium borohydride,sodium cyanoborohydride, tetramethyl ammonium borohydride, borane,diborane and the like) and the like, phosphorus compound (phosphorustrichloride, phosphorus tribromide, triphenylphosphine,triethylphosphine and the like) and the like.

The preferable reducing agent used in the catalytic reduction isconventional one, for example, platinum catalyst such as platinum plate,platinum sponge, platinum black, platinum colloid, platinum oxide andplatinum wire, palladium catalyst such as palladium sponge, palladiumblack, palladium oxide, palladium carbon, palladium colloid,palladium-barium sulfate and palladium-barium carbonate, nickel catalystsuch as reduing nickel, nickel oxide and Raney nickel, cobalt catalystsuch as reducing cobalt and Raney cobalt, iron catalyst such as reducingiron and Raney iron, copper catalyst such as reducing copper, Raneycopper and Ullmann copper, and the like.

The reducion is generally carried out in a solvent. Examples of thesolvent used include conventional solvent such as water, alcohol (e.g.,methanol, ethanol, propanol and the like), acetonitrile, diethyl ether,dioxane, N,N-dimethylformamide, tetrahydrofuran, liquid base or acid,and a mixed solvent thereof, and any other solvents that do notadversely affect the reaction. A liquid base or acid can be also used asa solvent. The reaction temperature is not particularly limited and thereaction generally proceeds under cooling to heating.

Production Method 5:

The objective compound (I-g) and a salt thereof can be produced bysubstituting the halogen of compound (I-f) or a salt thereof withcompound (V).

The preferable salts of compound (I-f) and (I-g) are exemplified bythose shown with regard to compound (I).

This reaction is preferably carried out in the presence of potassiumtert-butylate or a base such as the above-mentioned inorganic or organicbase. The reaction is preferably carried out in the presence of acatalyst such as tris(dibenzilideneacetone)-dipalladium(O),(R)-(+)-BINAP [2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] and thelike.

While the reaction temperature is not particularly limited, the reactionis preferably carried out from under room temperature to heating, andthe reaction can be also carried out in the presence of a solvent suchas toluene, which does not adversely affect the reaction.

Production Method 6:

The objective compound (I-h) and a salt thereof can be produced byacylation of compound (I-d) or a salt thereof.

The preferable salts of compound (I-f) are exemplified by those shownwith regard to compound (I).

When objective compound (I-f) is to be obtained by acylation, compound(I-d) having terminal amino is reacted with an acylating agent. Examplesof the acylating agent include lower alkanecarbonyl halide (e.g.,pivaloyl chloride) and lower alkanecarbonic anhydride. The solvent maybe dichloromethane, tetrahydrofuran and the like, and the reactionproceeds from under ice-cooling to room temperature.

Production Method 7:

The objective compound (I-c) and a salt thereof can be produced byintroducing an amino-protecting group into compound (I-d) or a saltthereof

Examples of the amino-protecting group include halogenated loweralkanecarbonate derivative (e.g., ethyl chlorocarbonate) and loweralkanecarbonic anhydride. The solvent may be dichloromethane,tetrahydrofuran and the like, and the reaction proceeds from underice-cooling to room temperature.

Production Method 8:

The objective compound (I-i) and a salt thereof can be produced bysulfonamidation of compound (I-d) or a salt thereof.

The preferable salts of compound (I-i) are exemplified by those shownwith regard to compound (I).

When the objective compound (I-i) is obtained by sulfonamidation,compound (I-d) having terminal amino is reacted with loweralkanesulfonyl halide (e.g., butanesulfonyl chloride), loweralkanesulfonic anhydride and the like. The solvent may bedichloromethane, tetrahydrofuran and the like, and the reaction proceedsfrom under ice-cooling to room temperature.

The aforementioned compounds can be converted to preferable salts asnecessary by a conventional method (e.g., the method described inExample 85 to be mentioned later). All of them can be purified asnecessary according to a conventional method for purifying an organiccompound (i.e., recrystallization, column chromatography, thin layerchromatography, high performance liquid chromatography and the like).The compound can be identified by NMR spectrum analysis, mass spectrumanalysis, IR spectrum analysis, elemental anlysis, melting pointmeasurement and the like.

The compound of the present invention may have one or more chrialcenters and, therefore, may be presented in enantiomers ordiastereomers. Some compounds having alkenyl may be present as a cis ortrans isomer. In bose case, the present invention encompasses mixturesthereof and respective isomers.

The inventive compound and a salt thereof may be in the form of asolvate, which is also encompassed in the present invention. The solvateis preferably exemplified by hydrate and ethanol solvate.

The pharmaceutical data of compound (I) are shown in the following todemonstrate the utility of the objective compound (I).

EXPERIMENTAL EXAMPLE 1 Blood Sugar Level Depressing Activity in db/dbMice

Test compound

Compound A

3-(2-Chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine(compound of Example 37)

Animal to be Used

Female C57BL/KsJ-dbm db+/db+, C57BL/KsJ-dbm +m/+m (Jackson Laboratory)mice (5 weeks old) were purchased and subjected to the test after 2-3weeks of acclimating period.

Drug Administration

The test drug was mixed with a powder diet (CE-2, Clea Japan, Inc.) in amortar. In the case of administration in 100 mg/kg, the mixingproportion was 0.1%, in the case of 30 mg/kg, the proportion was 0.03%and in the case of 10 mg/kg, the proportion was 0.01%. The diet waschanged twice a week for each group. The amount of the diet given andthe amount left were recorded and the diet intake was calculated bydetermining the difference.

Test Schedule

The female db/db mice were grouped according to body weight, blood sugarlevel and triglyceride concentration in plasma. Then, the drug-mixeddiet was given for 14 days, during which period the mice were 8 to 10weeks of age. At day 7 and day 14 in the morning, blood was taken fromorbital venous plexus using a heparinized glass capillary tube (ChaseHeparinized Capillary Tube), and centrifuged to give plasma fractions.The blood sugar level, triglyceride concentration in plasma and insulinconcentration in plasma were measured at day 0 and day 14, and bloodsugar level and triglyceride concentration in blood were measured at day7. Body weight was measured at day 0, day 7 and day 14. After finalblood sampling, the mice were sacrificed with CO₂ gas.

Measurement Method

Blood sugar level was measured using 10-15 μl of plasma and inaccordance with glucose oxidase method (glucose CII-Test Wako, Wako PureChemicals Co., Ltd.). The triglyceride concentration in plasma wasmeasured using 10-15 μl of plasma and in accordance withGPO-p-chlorophenol method (triglyceride G-Test Wako) or GPO-DAOS method(triglyceride E-Test Wako). The measurement was done promptly afterblood sampling. The insulin concentration in plasma was measured using20 μl of plasma (preservable at −20° C.) and in accordance with anantibody method (Phadesef Insulin RIA kit, Kabi Pharmacia).

Result

Using the difference between db/db mice control group and +/+mice inblood sugar level and triglyceride concentration in plasma as 100%, theproportion (%) of decrease in the blood sugar level and triglycerideconcentration in plasma of the group administered with the test drug wasdetermined. The results are shown in Table 1.

TABLE 1 Test compound Dose (mg/kg) Blood sugar decrease (%) Compound A 197

The compound (I) of the present invention can be used for therapeuticpurposes in the form of a pharmaceutical preparation. Thispharmaceutical preparation contains any one of the compounds (I) as anactive ingredient in admixture with a pharmaceutically acceptableorganic or inorganic excipient which is a solid, semi-solid or liquidand which is suitable for oral, parenteral or external (local)administration. Examples of the pharmaceutical preparation includecapsules, tablets, sugar coating tablets, granules, suppositories,liquid, lotion, suspension, emulsion, ointment, gel and the like. Whendesired, these preparations may contain adjuvant, auxiliary substance,stabilizer, moistening agent, emulsifier, buffering agent, and otherconventional additives. While the dose of the compound (I) variesdepending on the age and symptom of patients, compound (I) may beadministered for the therapy of the above-mentioned diseases in anaverage single dose amount of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg,250 mg, 500 mg or 1000 mg. In general, its daily dose may be about 0.1mg/patient to about 1000 mg/patient.

The present invention is described in more detail by way of thefollowing Preparation Examples and Examples.

PREPARATION EXAMPLE 1-1

To a solution of diisopropylamine (7.4 ml) in tetrahydro-furan (36 ml)was added dropwise a 1.6 M solution (30 ml) of 1-butyllithium inn-hexane under a nitrogen atmosphere at an inside temperature of from−62° C. to −48° C. over 5 minutes. After stirring for 30 min underice-cooling, a solution of N-tert-butylmethane-sulfonamide (3.63 g) intetrahydrofuran (15 ml) was added dropwise at an inside temperature offrom −60° C. to −50° C. over 5 minutes. After stirring for 1 hr underice-cooling, the mixture was cooled to an inner temperature of −60° C.again. 4-Formyl-pyridine (2.74 ml) was added dropwise and after stirringat room temperature for 5 hr, the mixture was left standing overnight.Water (250 ml) was gradually added to the reaction mixture underice-cooling, and the mixture was extracted 4 times with ethyl acetate.The organic layers were combined and dried over magnesium sulfate andconcentrated to dryness under reduced pressure to giveN-tert-butyl-2-hydroxy-2-(4-pyridyl)ethane-sulfonamide (7.02 g) as abrown oil.

MASS(ESI): m/z 259(M+1).

PREPARATION EXAMPLE 1-2

A mixture of N-tert-butyl-2-hydroxy-2-(4-pyridyl)ethane-sulfonamide(6.62 g), acetic anhydride (13.2 ml) and pyridine (26.4 ml) was stirredat room temperature for 1.5 hr. To the reaction mixture was added1,8-diazabicyclo[5.4.0]undec-7-ene (9.58 ml), and the mixture wasstirred in an oil bath at 100° C. for 40 min. The reaction mixture wasconcentrated to dryness under reduced pressure. The residue wasdissolved in ethyl acetate and washed with saturated brine. Th aqueouslayer was extracted with ethyl acetate and organic layers were combined,dried over magnesium sulfate and concentrated to dryness under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1) to give(E)-N-tert-butyl-2-(4-pyridyl)ethenesulfonamide (3.91 g) as apale-yellow solid.

¹H-NMR(CDCl₃): 1.38(9H, s), 6.99(1H, d, J=16 Hz), 7.33(2H, d, J=6 Hz),7.39(1H, d, J=16 Hz), 8.68(2H, d, J=6 Hz). MASS(ESI): m/z 241(M+1).

PREPARATION EXAMPLE 1-3

(E)-N-tert-Butyl-2-(4-pyridyl)ethenesulfonamide (3.8 g) was dissolved intrifluoroacetic acid (38 ml) and the mixture was stirred in an oil bathat 50° C. for 4 hr. The reaction mixture was concentrated to drynessunder reduced pressure. The residue was dissolved in trifluoroaceticacid (19 ml) and stirred in an oil bath at 50° C. for 45 min. Thereaction mixture was concentrated to dryness under reduced pressure andthe residue was partitioned between chloroform:methanol(9:1) and asaturated aqueous solution of sodium hydrogen carbonate. The aqueouslayer was extracted twice with chloroform:methanol(9:1) and once withethyl acetate. The aqueous layer was saturated with sodium chloride andextracted 4 times with ethyl acetate. All extracts with ethyl acetatewere combined, dried over magnesium sulfate, and concentrated to drynessunder reduced pressure. The residue was powdered from diethyl ether togive (E)-2-(4-pyridyl)ethene-sulfonamide(2.34 g) as a pale-brown powder.

¹H-NMR(DMSO-d₆): 7.27(2H, s), 7.31(1H, d, J=16 Hz), 7.55(1H, d, J=16Hz), 7.67(2H, d, J=6 Hz), 8.63(2H, d, J=6 Hz). MASS(ESI): m/z 183(M−1).

PREPARATION EXAMPLE 2-1

To a solution of diisopropylamine (3.7 ml) in tetrahydrofuran (18 ml)was added dropwise a 1.6 M solution (15 ml) of 1-butyllithium inn-hexane under a nitrogen atmosphere at an inside temperature of from−62° C. to −48° C. over 5 minutes. After stirring for 30 min underice-cooling, a solution of N-tert-butylmethanesulfonamide(3.63 g) intetrahydrofuran (12 ml) was added dropwise at an inside temperature offrom −63° C. to −59° C. over 5 minutes. After stirring for 1 hr underice-cooling, the mixture was cooled to an inner temperature of −60° C.again. 1-Bromo-3-(tert-butyldimethylsilyloxy)propane (3.35 ml) was addeddropwise and the mixture was stirrd overnight at room temperature. Thereaction mixture was partitioned between ethyl acetate and saturatedbrine and the organic layer was dried over magnesium sulfate andconcentrated to dryness under reduced pressure. The residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=9:1) to giveN-tert-butyl-4-(tert-butyl-dimethylsilyloxy)butanesulfonamide (618 mg)as a pale-yellow oil.

¹H-NMR(CDCl₃): 0.07(6H, s), 0.89(9H, s), 1.38(9H, s), 1.64(2H, m),1.90(2H, m), 3.08(2H, t, J=6 Hz), 3.64(2H, t, J=6 Hz), 4.05(1H, br s).MASS(ESI): m/z 322(M−1).

PREPARATION EXAMPLE 2-2

N-tert-Butyl-4-(tert-butyldimethylsilyloxy)butanesulfonamide (515 mg)was dissolved in tetrahydrofuran (2.0 ml), a 1N solution (3.2 ml) oftetrabutylammonium fluoride in tetrahydrofuran was added and the mixturewas left standing for 2 hr. The reaction mixture was partitioned betweenethyl acetate and 1N hydrochloric acid saturated with sodium chloride.The aqueous layer was extracted twice with ethyl acetate. The organiclayers were combined, dried over magnesium sulfate, and concentrated todryness under reduced pressure to give a crude product (1.17 g) ofN-tert-butyl-4-hydroxybutanesulfonamide as a pale-yellow oil. This wasused in the next reaction without futher purification.

PREPARATION EXAMPLE 2-3

A crude product (1.17 g) of N-tert-butyl-4-hydroxybutane-sulfonamide wasdissolved in pyridine (3.0 ml) and acetic anhydride (1.5 ml) was added,and the mixture was left standing at room temperature for 1 hr. Thereaction mixture was concentrated to dryness under reduced pressure andthe residue was partitioned between ethyl acetate and 1N hydrochloricacid. The organic layer was washed once with water and once withsaturated brine, dried over magnesium sulfate and concentrated todryness under reduced pressure to giveN-tert-butyl-4-acetoxybutanesulfonamide (425 mg) as a pale-yellow oil.

¹H-NMR(CDCl₃): 1.38(9H, s), 1.78(2H, m), 1.90(2H, m), 2.05(3H, s),3.08(2H, t, J=6 Hz), 4.10(2H, t, J=6 Hz), 4.05(1H, br s). MASS(ESI): m/z322(M−1).

PREPARATION EXAMPLE 2-4

N-tert-Butyl-4-acetoxybutanesulfonamide (425 mg) was dissolved intrifluoroacetic acid (4.3 ml), and the mixture was stirred at roomtemperature for 4 hr and concentrated to dryness under reduced pressure.The residue was purified by silica gel column chromatography(chloroform:methanol=49:1) to give 4-acetoxybutanesulfonamide (347 mg)as a brown oil.

¹H-NMR(CDCl₃): 1.80(2H, m), 1.96(2H, m), 2.08(3H, s), 3.16(2H, t, J=6Hz), 4.11(2H, t, J=6 Hz), 4.77(2H, br s). MASS(ESI): m/z 194(M−1).

PREPARATION EXAMPLE 3-1

To a suspension of tetrakis(triphenylphosphine)palladium (213 mg) intoluene (7 ml) was added 2-chloro-4-iodotoluene (2.33 g) at roomtemperature. The mixture was stirred at room temperature for 30 min, anda solution of phenylboronic acid (1.35 g) in ethanol (2 ml) and 2 Maqueous sodium carbonate solution (9.25 ml) were added to this mixture,which was followed by reflux under heating. After 3 hr, the reactionmixture was cooled and the organic layer was separated. The aqueouslayer was extracted with hexane (4 ml). The organic layers werecombined, washed with saturated aqueous sodium hydrogen carbonatesolution (4 ml) and saturated brine (4 ml), and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated. Tothe residue (2.11 g) were added hexane (10 ml) and silica gel (4 g) andthe mixture was stirred at room temperature for 1 hr. Silica gel wasfiltered off and the filtrate was concentrated to give2-chloro-4-phenyltoluene as a pale-brown oil (1.86 g, 99.4%).

¹H-NMR(CDCl₃): 2.40(3H, s), 7.23-7.60(8H, m).

PREPARATION EXAMPLE 3-2

In the same manner as in Preparation Example 4-2 to be mentioned later,2-chloro-4-phenylbenzylbromide was obtained as colorless crystals (3.22g) from 2-chloro-4-phenyltoluene (3.6 g).

¹H-NMR(CDCl₃): 4.64(2H, s), 7.35-7.63(8H, m). m.p. 73-74° C.

PREPARATION EXAMPLE 3-3

In the same manner as in Preparation Example 4-5 to be mentioned later,6-bromo-2-[N-(2-chloro-4-phenylbenzyl)acetamido]-3-nitropyridine (1.6 g)was obtained as amorphous from 2-(acetamido)-6-bromo-3-nitropyridine(1.0 g) and 2-chloro-4-phenylbenzylbromide (1.1 g).

¹H-NMR(CDCl₃): 2.25(3H, br s), 5.42(2H, br s), 7.32-7.70(9H, m),8.11(1H,d, J=8 Hz). MASS(ESI): m/z 458(M−1).

PREPARATION EXAMPLE 3-4

To a solution of2-[N-acetyl-N-(2-chloro-4-phenylbenzyl)]-amino-6-bromo-3-nitropyridine(3.56 g) in acetic acid (7.1 ml) and ethanol (34 ml) was added ironpowder (1.73 g) at room temperature under a nitrogen flow and themixture was refluxed under heating. One hour later, the reaction mixturewas cooled and dichloromethane:methanol=5:1 (17.5 ml) was added, whichwas followed by stirring at room temperature for 15 min. The reactionmixture was filtered through celite and washed 10 times withdichloromethane (7 ml). The filtrate was concentrated and subjected toazeotropic distillation once with toluene. To the residue were addeddichloromethane (17.5 ml) and saturated aqueous sodium hydrogencarbonate solution (20 ml) and the mixture was stirred at roomtemperature for 10 min. This mixture was filtered through celite andwashed 10 times with dichloromethane (7 ml). The organic layer wasseparated and washed with saturated brine. The organic layer was driedover anhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated to give the residue as a colorless solid (3.39 g). This wassuspended in methanol (17 ml), heated and stirred at room temperaturefor 30 min. The crystals were filtrated, washed 4 times with methanol(3.4 ml) and dried under reduced pressure at 50° C. for 2 hr to give5-bromo-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridineas pale-yellow crystals (2.8 g, 87.8%).

¹H-NMR(CDCl₃): 2.61(3H, s), 5.62(2H, s), 6.71(1H, d, J=8 Hz),7.32-7.55(7H, m), 7.68(1H, s), 7.92(1H, d, J=8 Hz). MASS(ESI): m/z414(M−1).

PREPARATION EXAMPLE 3-5

In the same manner as in Preparation Example 12-2 to be mentioned later,methyl3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(504 mg) was obtained as pale-yellow crystals from5-bromo-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine(822 mg).

¹H-NMR(CDCl₃): 2.60(3H, s), 4.00(3H, s), 5.73(2H, s), 6.71(1H, d, J=8Hz), 7.30-7.54(6H, m), 7.67(1H, br s), 8.10(1H, d, J=8 Hz), 8.18(1H, d,J=8 Hz). MASS(ESI): m/z 392(M+1). m.p. 200-201° C.

PREPARATION EXAMPLE 3-6

In the same manner as in Preparation Example 14-7 to be mentioned later,3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (403 mg) was obtained as colorless crystals from methyl3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(500 mg).

¹H-NMR(DMSO-d₆): 2.55(3H ,s), 5.65(2H, s), 6.60(1H, d, J=8 Hz),7.33-7.55(3H, m), 7.65(2H, br d, J=8 Hz), 7.85(1H, d, J=1 Hz), 8.00(1H,d, J=8 Hz), 8.11(1H, d, J=8 Hz). MASS(ESI): m/z 376(M-1). m.p. 238-243°C.

PREPARATION EXAMPLE 4-1

Acetic anhydride (430 mg) and pyridine (416 mg) were added to a solutionof 3-chloro-4-methylphenol (500 mg) in ether (5.0 ml), and the mixturewas stirred at room temperature for 2 hr. The reaction mixture waswashed once with 1N hydrochloric acid and twice with saturated brine,dried over magnesium sulfate, and concentrated to dryness under reducedpressure to give 4-acetoxy-2-chlorotoluene as a pale-yellow oil (645mg).

¹H-NMR(CDCl₃): 2.30(3H, s), 2.36(3H, s), 6.90(1H, dd, J=8,2 Hz),7.12(1H, d, J=2 Hz), 7.22(1H, d, J=8 Hz).

PREPARATION EXAMPLE 4-2

To a solution of 4-acetoxy-2-chlorotoluene (13.4 g) in carbontetrachloride (134 ml) were added N-bromosuccinimide (12.9 g) and2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (1.12 g), and themixture was refluxed under heating for 2.5 hr. The reaction mixture wasconcentrated to dryness under reduced pressure. To the residue was addedhexane (270 ml) and the mixture was stirred at room temperature for 10min. The insoluble matter was filtered off and washed with hexane. Thefiltrate and washing were combined and washed 3 times with saturatedaqueous sodium hydrogen carbonate solution and once with saturatedbrine. The organic layer was dried over magnesium sulfate andconcentrated to dryness under reduced pressure. The residue wascrystallized from hexane to give 4-acetoxy-2-chlorobenzylbromide ascolorless crystals (11.3 g).

¹H-NMR(CDCl₃): 2.30(3H, s), 4.58(2H, s), 7.02(1H, dd, J=8,2 Hz),7.18(1H, d, J=2 Hz), 7.44(1H, d, J=8 Hz).

PREPARATION EXAMPLE 4-3

To a suspension of 2,6-dibromo-3-nitropyridine (5.00 g) in ethanol (10ml) was added a solution (6.8 M, 15 ml) of ammonium/ethanol at roomtemperature, and the mixture was stirred at room temperature for 19 hrin a sealed container. Water (25 ml) was added to the reaction mixture,and the precipitate was collected by filtration and washed with ethanol.This was suspended in ethanol (55 ml), heated, and allowed to cool. Theprecipitate was collected by filtration to give2-amino-6-bromo-3-nitropyridine as a yellow powder (3.19 g).

¹H-NMR(DMSO-d₆): 6.89(1H, d, J=8 Hz), 8.24(1H, d, J=8 Hz), 8.25(2H, brs). MASS(ESI): m/e 216,218(M−H)⁻.

PREPARATION EXAMPLE 4-4

To a suspension of 2-amino-6-bromo-3-nitropyridine (23.9 g) in aceticacid (48 ml) were added acetic anhydride (48 ml) and sulfuric acid (2.9ml), and the mixture was heated at 65° C. for 40 min. The reactionmixture once became homogeneous and a product soon precipitated to givea suspension. The reaction mixture was allowed to cool and poured intocold water (480 ml), which was followed by stirring for 30 min. Theprecipitate was collected by filtration and washed with water to give acrude product. This was suspended in ether (60 ml) and collected byfiltration to give 2-(acetamido)-6-bromo-3-nitropyridine as apale-yellow powder (27.2 g).

¹H-NMR(CDCl₃): 2.54(3H s), 7.33(1H, d, J=8 Hz), 8.33(1H, d, J=8 Hz),9.95(1H, br s). MASS(ESI): m/e 258,260(M−H)⁻.

PREPARATION EXAMPLE 4-5

To a solution of 2-acetamido-6-bromo-3-nitropyridine (203 mg) inN,N-dimethylformamide (2.34 ml) was added sodium hydride (60%, 34.3 mg)under ice-cooling, and the mixture was stirred for 1 hr.4-Acetoxy-2-chlorobenzylbromide (288 mg) was added, and the mixture wasstirred for 30 min under ice-cooling and at room temperature for 1 hr.Ethyl acetate (350 ml) and water (700 ml) were added to the reactionmixture under ice-cooling, and the mixture was partitioned. The organiclayer was washed with water and saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified by flash silica gel columnchromatography and eluted with hexane/ethyl acetate=4/1-3/1. The eluatewas concentrated under reduced pressure to give2-[N-(4-acetoxy-2-chlorobenzyl)acetamido]-6-bromo-3-nitropyridine as anoil (256 mg).

¹H-NMR(CDCl₃): 2.22(3H, br s), 2.29(3H, s), 5.37(2H, br s), 7.02(1H, dd,J=1,8 Hz), 7.19(1H, br s), 7.50(1H, br s), 7.64(1H, d, J=8 Hz), 8.10(1H,d, J=8 Hz).

PREPARATION EXAMPLE 4-6

To a solution of2-[N-(4-acetoxy-2-chlorobenzyl)acetamido]-6-bromo-3-nitropyridine (1.28g) in ethanol (13 ml) were added acetic acid (1.5 ml) and reduced ironpowder (646 mg), and the mixture was refluxed under heating at 110° C.for 15 hr. After allowing to cool, chloroform/methanol=10/1 (15 ml) wasadded and the mixture was stirred under ice-cooling. The insolublematter was filtered off and the filtrate was concentrated. A saturatedaqueous sodium hydrogen carbonate solution (5 ml) andchloroform/methanol=10/1 (15 ml) were added to make the mixturealkaline, and the precipitated insoluble matter was filtered off. Theresidue was repeatedly eluted with chloroform/methanol=5/1-2/1-1/1. Theorganic layer of the filtrate was washed with saturated aqueous sodiumhydrogen carbonate solution and saturated brine, dried over anhydrousmagnesium sulfate, filtered and concentrated. To the resulting crystalswas added ethyl acetate (8 ml), and the mixture was heated and stirredat room temperature. The crystals were collected by filtration and driedunder reduced pressure to give5-bromo-3-(2-chloro-4-hydroxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridineas colorless crystals (1.04 g).

¹H-NMR(DMSO-d₆): 2.46(3H, s), 5.40(2H, s), 6.53(1H, d, J=8 Hz), 6.66(1H,dd, J=1,8 Hz), 6.91(1H, d, J=1 Hz), 7.44(1H, d, J=8 Hz), 7.97(1H, d, J=8Hz).

PREPARATION EXAMPLE 4-7

In the same manner as in Preparation Example 12-2 to be mentioned later,methyl3-(2-chloro-4-hydroxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as pale-gray crystals (272 mg) from5-bromo-3-(2-chloro-4-hydroxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine(400 mg).

¹H-NMR(DMSO-d₆): 2.52(3H, s), 3.86(3H, s), 5.50(2H, s), 6.50(1H, d, J=8Hz), 6.64(1H, dd, J=8,2 Hz), 6.92(1H, d, J=2 Hz), 8.04(1H, d, J=8 Hz),8.16(1H, d, J=8 Hz), 10.00(1H, br s).

PREPARATION EXAMPLE 4-8

In the same manner as in Preparation Example 14-6, methyl3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbxylatewas obtained as bright yellow crystals (536 mg) from methyl3-(2-chloro-4-hydroxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(560 mg) and methyl iodide (359 mg).

¹H-NMR(CDCl₃): 2.54(3H, s), 3.77(3H, s), 4.00(3H, s), 5.62(2H, s),6.66(2H, s), 6.97(1H, d, J=1 Hz), 8.05(1H, d, J=8 Hz), 8.14(1H, d, J=8Hz). MASS(ESI): m/z 346(M+1).

PREPARATION EXAMPLE 4-9

In the same manner as in Preparation Example 14-7 to be mentioned later,3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (83 mg) was obtained as a pale-yellow powder from methyl3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(78 mg).

¹H-NMR(DMSO-d₆): 2.50(3H, s), 3.55(3H, s), 5.53(2H, s), 6.58(1H, d, J=8Hz), 6.81(1H, dd, J=8 and 2 Hz), 7.13(1H, d, J=2 Hz), 7.99(1H, d, J=8Hz), 8.11(1H, d, J=8 Hz). MASS(ESI): m/e 330(M−H)⁻.

PREPARATION EXAMPLE 5-1

In the same manner as in Preparation Example 14-6 to be mentioned later,methyl3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as thin yellow crystals (578 mg) from methyl3-(2-chloro-4-hydroxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(560 mg) and ethyl iodide (395 mg).

¹H-NMR(CDCl₃): 1.39(3H, t, J=7 Hz), 2.53(3H, s), 3.98(2H, q, J=7 Hz),4.00(3H, s), 5.62(2H, s), 6.64(2H, s), 6.96(1H, s), 8.05(1H, d, J=8 Hz),8.14(1H, d, J=8 Hz). MASS(ESI): m/z 360(M+1).

PREPARATION EXAMPLE 5-2

In the same manner as in Preparation Example 14-7 to be mentioned later,3-(2-chloro-4-ethoxy)benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (380 mg) from methyl3-(2-chloro-4-ethoxy)benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(376 mg).

¹H-NMR(DMSO-d₆): 1.21(3H, t, J=7.5 Hz), 2.52(3H, s), 2.99(2H, q, J=7.5Hz), 5.57(2H, s), 6.50(1H, d, J=8 Hz), 7.15(1H, dd, J=8, 1 Hz), 7.47(1H,d, J=1 Hz), 8.00(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz).

PREPARATION EXAMPLE 6-1

In the same manner as in Preparation Example 14-6 to be mentioned later,methyl3-[2-chloro-4-(1-propoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as colorless crystals (220 mg) from methyl3-[2-chloro-4-hydroxy-benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(240 mg).

¹H-NMR(CDCl₃): 1.01(3H, t, J=7 Hz), 1.70-1.85(2H, m), 2.53(3H, s),3.86(2H, t, J=7 Hz), 4.00(3H, s), 5.61(2H, s), 6.63(2H, s), 6.96(1H, brs), 8.04(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz). MASS(ESI): m/z 374(M+1).

PREPARATION EXAMPLE 6-2

In the same manner as in Preparation Example 14-7 to be mentioned later,3-[2-chloro-4-(1-propoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (205 mg) from methyl3-[2-chloro-4-(1-propoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(247 mg).

¹H-NMR(DMSO-d₆): 0.93(3H, t, J=7 Hz), 1.62-1.76(2H, m), 2.51(3H, s),3.91(2H, t, J=7 Hz), 5.54(2H, s), 6.56(1H, d, J=8 Hz), 6.81(1H, dd, J=8,2 Hz), 7.13(1H, d, J=2 Hz), 8.00(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz).MASS(ESI): m/z 358(M−1).

PREPARATION EXAMPLE 7-1

In the same manner as in Preparation Example 14-6 to be mentioned later,methyl3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as thin yellow crystals (635 mg) from methyl3-(2-chloro-4-hydroxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(687 mg) and 2-iodopropane (528 mg).

¹H-NMR(CDCl₃): 1.30(6H, d, J=7 Hz), 2.54(3H, s), 4.00(3H, s), 4.48(1H,sept, J=7 Hz), 5.61(2H, s), 6.62(2H, s), 6.95(1H, s), 8.05(1H, d, J=8Hz), 8.14(1H, d, J=8 Hz). MASS(ESI): m/z 374(M+1).

PREPARATION EXAMPLE 7-2

In the same manner as in Preparation Example 14-7 to be mentioned later,3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (66 mg) was obtained as pale-yellow powder from methyl3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(67 mg).

¹H-NMR(DMSO-d₆): 1.23(6H, d, J=7 Hz), 2.50(3H, s), 4.60(1H, sept, J=7Hz), 5.53(2H, s), 6.52(1H, d, J=8 Hz), 6.79(1H, dd, J=8 and 2 Hz),7.11(1H, d, J=2 Hz), 8.01(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz).MASS(ESI): m/e 358(M−H)⁻.

PREPARATION EXAMPLE 8-1

In the same manner as in Preparation Example 14-6 to be mentioned later,methyl3-(4-(1-butoxy)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as thin green crystals (778 mg) from methyl3-(2-chloro-4-hydroxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(800 mg) and 1-iodobutane (666 mg).

¹H-NMR(CDCl₃): 0.96(3H, t, J=7 Hz), 1.40-1.52(2H, m), 1.68-1.80(2H, m),2.53(3H, s), 3.90(2H, t, J=7 Hz), 4.00(3H, s), 5.62(2H, s), 6.64(2H, s),6.96(1H, s), 8.05(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz). MASS(ESI): m/z388(M+1).

PREPARATION EXAMPLE 8-2

In the same manner as in Preparation Example 14-7 to be mentioned later,3-(4-(1-butoxy)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid(90 mg) was obtained as a pale-yellow powder from methyl3-(4-(1-butoxy)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(90 mg).

¹H-NMR(DMSO-d₆): 0.90(3H, t, J=7 Hz), 1.30-1.48(2H, m), 1.57-1.71(2H,m), 2.50(3H, s), 3.94(2H, t, J=7 Hz), 5.54(2H, s), 6.53(1H, d, J=8 Hz),6.80(1H, dd, J=8 and 2 Hz), 7.13(1H, d, J=2 Hz), 8.00(1H, d, J=8 Hz),8.11(1H, d, J=8 Hz). MASS(ESI): m/e 372(M−H)⁻.

PREPARATION EXAMPLE 9-1

In the same manner as in Preparation Example 14-6 to be mentioned later,methyl3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as colorless crystals (247 mg) from methyl3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(240 mg).

¹H-NMR(CDCl₃): 0.92(3H, brt, J=7 Hz), 1.29-1.48(4H, m), 1.69-1.81(2H,m), 2.53(3H, s), 3.89(2H, t, J=7 Hz), 4.00(3H, s), 5.61(2H, s), 6.63(2H,s), 6.96(1H, br s), 8.04(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz). MASS(ESI):m/z 402(M+1).

PREPARATION EXAMPLE 9-2

In the same manner as in Preparation Example 14-7 to be mentioned later,3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (208 mg) from methyl3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(247 mg).

¹H-NMR(DMSO-d₆): 0.87(3H, t, J=7 Hz), 1.27-1.41(6H, m), 1.61-1.72(2H,m), 2.50(3H, s), 3.94(2H, t, J=7 Hz), 5.53(2H, s), 6.55(1H, d, J=8 Hz),6.80(1H, dd, J=8, 2 Hz), 7.13(1H, d, J=2 Hz), 8.00(1H, d, J=8 Hz),8.12(1H, d, J=8 Hz). MASS(ESI): m/z 386(M−1).

PREPARATION EXAMPLE 10-1

In the same manner as in Preparation Example 14-6 to be mentioned later,methyl3-[2-chloro-4-(cyclopentylmethyloxy)-benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as colorless amorphous (83 mg) from methyl3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(240 mg).

¹H-NMR(CDCl₃): 1.22-1.41(3H, m), 1.50-1.70(3H, m), 1.75-1.90(2H, m),2.33(1H, m), 2.53(3H, s), 3.77(2H, d, J=5 Hz), 4.00(3H, s), 5.62(2H, s),6.64(2H, s), 6.97(1H, br s), 8.05(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz).MASS(ESI): m/z 414(M+1).

PREPARATION EXAMPLE 10-2

In the same manner as in Preparation Example 14-7 to be mentioned later,3-[2-chloro-4-(cyclopentylmethyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (72 mg) from methyl3-[2-chloro-4-(cyclopentylmethyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(82 mg).

¹H-NMR(CDCl₃): 1.24-1.41(3H, m), 1.50-1.70(3H, m), 1.75-1.90(2H, m),2.33(1H, m), 2.64(3H, s), 3.79(2H, d, J=5 Hz), 5.53(2H, s), 6.67(1H, d,J=8 Hz), 6.70(1H, dd, J=8, 2 Hz), 7.00(1H, d, J=2 Hz), 8.15(1H, d, J=8Hz), 8.21(1H, d, J=8 Hz). MASS(ESI): m/z 398(M−1).

PREPARATION EXAMPLE 11-1

A mixture of 2-amino-6-bromo-3-nitropyridine (4.5 g), propionic acidanhydride (12.2 ml), propionic acid (12.2 ml) and conc. sulfuric acid(101 mg) was stirred in an oil bath at 65° C. for 30 min, and leftstanding overnight. Water (122 ml) was added to the reaction mixtureunder ice-cooling, and stirred at the same temperature for 30 min. Theprecipitate was collected by filtration, washed with water, suspended indiisopropyl ether (20 ml) and stirred at room temperature for 30 min.The precipitate was stirred and washed with diisopropyl ether to give6-bromo-3-nitro-2-(propionylamino)pyridine (5.59 g) as a pale-brownpowder.

¹H-NMR(CDCl₃): 1.27(3H, t, J=6 Hz), 2.78(2H, q, J=6 Hz), 7.34(1H, d, J=8Hz), 8.32(1H, d, J=8 Hz), 9.86(1H, br. s). MASS(ESI): m/z 275(M+1).

PREPARATION EXAMPLE 11-2

In the same manner as in Preparation Example 4-5,2-[N-(4-acetoxy-2-chlorobenzyl)propionylamino]-6-bromo-3-nitropyridinewas obtained as a pale-yellow powder (7.06 g) from6-bromo-3-nitro-2-(propionylamino)pyridine (5.59 g) and4-acetoxy-2-chlorobenzylbromide (8.06 g).

¹H-NMR(CDCl₃): 1.13(3H, t, J=6 Hz), 2.29(3H, s), 2.42(2H, br s),5.34(2H, br s), 7.02(1H, dd, J=8, 2 Hz), 7.17(1H, br s), 7.50(1H, br s),7.63(1H, d, J=8 Hz), 8.10(1H, d, J=8 Hz). MASS(ESI): m/z 458(M+1).

PREPARATION EXAMPLE 11-3

In the same manner as in Preparation Example 4-6,5-bromo-3-(2-chloro-4-hydroxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (440 mg) from2-[N-(4-acetoxy-2-chlorobenzyl)propionylamino]-6-bromo-3-nitropyridine(695 mg).

¹H-NMR(DMSO-d₆): 1.24(3H, t, J=7 Hz), 2.76(2H, q, J=7 Hz), 5.40(2H, s),6.49(1H, d, J=8 Hz), 6.65(1H, dd, J=1, 8 Hz), 6.90(1H, d, J=1 Hz),7.45(1H, d, J=8 Hz), 8.00(1H, d, J=8 Hz). MASS(ESI): m/z 366,368(M+1).

PREPARATION EXAMPLE 11-4

In the same manner as in Preparation Example 14-6 to be mentioned later,5-bromo-3-(2-chloro-4-ethoxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridinewas obtained as thin yellow crystals (928 mg) from5-bromo-3-(2-chloro-4-hydroxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine(1.1 g) and ethyl iodide (936 mg).

¹H-NMR(CDCl₃): 1.36(3H, t, J=7 Hz), 1.39(3H, t, J=7 Hz), 2.75(2H, q, J=7Hz), 3.98(2H, q, J=7 Hz), 5.49(2H, s), 6.55(1H, d, J=8 Hz), 6.65(1H, dd,J=1,8 Hz), 6.95(1H, d, J=1 Hz), 7.37(1H, d, J=8 Hz), 7.88(1H, d, J=8Hz). MASS(ESI): m/z 394,396(M+1).

PREPARATION EXAMPLE 11-5

In the same manner as in Preparation Example 12-2 to be mentioned later,methyl3-(2-chloro-4-ethoxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as colorless crystals (697 mg) from5-bromo-3-(2-chloro-4-ethoxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine(908 mg).

¹H-NMR(CDCl₃): 1.37-1.42(6H, m), 2.80(2H, q, J=7 Hz), 3.91-4.02(5H, m),5.62(2H, s), 6.58(1H, d, J=8 Hz), 6.63(1H, dd, J=1,8 Hz), 6.95(1H, d,J=1 Hz), 8.09(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz). MASS(ESI): m/z374(M+1).

PREPARATION EXAMPLE 11-6

In the same manner as in Preparation Example 14-7 to be mentioned later,3-(2-chloro-4-ethoxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (369 mg) from methyl3-(2-chloro-4-ethoxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(407 mg).

¹H-NMR(DMSO-d₆): 1.26(3H, t, J=7 Hz), 1.29(3H, t, J=7 Hz), 2.81(2H, q,J=7 Hz), 4.01(2H, q, J=7 Hz), 5.55(2H, s), 6.53(1H, d, J=8 Hz), 6.80(1H,dd, J=1,8 Hz), 7.12(1H, d, J=1 Hz), 8.01(1H, d, J=8 Hz), 8.15(1H, d, J=8Hz). MASS(ESI): m/z 358(M−1).

PREPARATION EXAMPLE 12-1

In the same manner as in Preparation Example 14-6 to be mentioned later,5-bromo-3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridinewas obtained as thin yellow crystals (1.10 g) from5-bromo-3-(2-chloro-4-hydroxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine(1.1 g) and (1-propyl)iodide (663 mg).

¹H-NMR(CDCl₃): 1.01(3H, t, J=7 Hz), 1.36(3H, t, J=7 Hz), 1.71-1.85(2H,m), 2.75(2H, q, J=7 Hz), 3.87(2H, t, J=7 Hz), 5.49(2H, s), 6.54(1H, d,J=8 Hz), 6.65(1H, dd, J=1,8 Hz), 6.96(1H, d, J=1 Hz), 7.37(1H, d, J=8Hz), 7.88(1H, d, J=8 Hz). MASS(ESI): m/z 408,410(M+1).

PREPARATION EXAMPLE 12-2

N,N-Dimethylformamide (6 ml), triethylamine(0.85 ml),1,3-bis(diphenylphosphino)propane (346 mg), palladium (II) acetate (188mg) and methanol(4 ml) were added to5-bromo-3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine(1.07 g) and the mixture was stirred for 8 hr while heating to 85° C. ina 10 atm. carbon monoxide atmosphere. After cooling with ice, water (20ml) was added to the reaction mixture and the reaction mixture wasstirred at room temperature. The precipitated crystals were collected byfiltration, washed with water and air-dried. This was applied to silicagel column chromatography, eluted with hexane/ethyl acetate=1/1, andconcentrated under reduced pressure. Methanol (5 ml) was added to theobtained crystals and heated on a hot water bath. The mixture wasstirred under ice-cooling, and the precipitate was collected byfiltration and washed with cooled methanol to give methyl3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylateas bright yellow crystals (816 mg).

¹H-NMR(CDCl₃): 1.01(3H, t, J=7 Hz), 1.38(3H, t, J=7 Hz), 1.70-1.85(2H,m), 2.80(2H, q, J=7 Hz), 3.86(2H, t, J=7 Hz), 4.00(3H, s), 5.62(2H, s),6.58(1H, d, J=8 Hz), 6.68(1H, dd, J=1, 8 Hz), 6.96(1H, d, J=1 Hz),8.09(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz). MASS(ESI): m/z 388(M+1).

PREPARATION EXAMPLE 12-3

In the same manner as in Preparation Example 14-7 to be mentioned later,3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (620 mg) from methyl3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(789 mg).

¹H-NMR(CDCl₃): 1.02(3H, t, J=7 Hz), 1.44(3H, t, J=7 Hz), 1.71-1.86(2H,m), 2.90(2H, q, J=7 Hz), 3.88(2H, t, J=7 Hz), 5.54(2H, s), 6.60(1H, d,J=8 Hz), 6.38(1H, dd, J=1, 8 Hz), 7.00(1H, d, J=1 Hz), 8.15-8.24(2H, m).MASS(ESI): m/z 372(M−1).

PREPARATION EXAMPLE 13-1

In the same manner as in Preparation Example 14-6 to be mentioned later,5-bromo-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridinewas obtained as thin yellow crystals (789 mg) from5-bromo-3-(2-chloro-4-hydroxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine(1.1 g) and (1-pentyl)iodide (772 mg).

¹H-NMR(CDCl₃): 0.92(3H, t, J=7 Hz), 1.28-1.48(7H, m), 1.66-1.82(2H, m),2.75(2H, q, J=7 Hz), 3.90(2H, t, J=7 Hz), 5.49(2H, s), 6.55(1H, d, J=8Hz), 6.65(1H, dd, J=1,8 Hz), 6.95(1H, d, J=1 Hz), 7.37(1H, d, J=8 Hz),7.86(1H, d, J=8 Hz). MASS(ESI): m/z 436,438(M+1).

PREPARATION EXAMPLE 13-2

In the same manner as in Preparation Example 12-2, methyl3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as colorless crystals (537 mg) from5-bromo-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine(772 mg).

¹H-NMR(CDCl₃): 0.85-0.98(3H, m), 1.29-1.49(7H, m), 1.68-1.82(2H, m),2.80(2H, q, J=7 Hz), 3.90(2H, t, J=7 Hz), 4.00(3H, s), 5.62(2H, s),6.53-6.66(2H, m), 6.95(1H, d, J=1 Hz), 8.05-8.16(2H, m). MASS(ESI): m/z416(M+1).

PREPARATION EXAMPLE 13-3

In the same manner as in Preparation Example 14-7 to be mentioned later,3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (428 mg) from methyl3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(525 mg).

¹H-NMR(CDCl₃): 0.92(3H, t, J=7 Hz), 1.30-1.50(7H, m), 1.70-1.82(2H, m),2.90(2H, q, J=7 Hz), 3.91(2H, t, J=7 Hz), 5.53(2H, s), 6.60(1H, d, J=8Hz), 6.68(1H, dd, J=1, 8 Hz), 7.00(1H, d, J=1 Hz), 8.15-8.25(2H, m).MASS(ESI): m/z 400(M−1).

PREPARATION EXAMPLE 14-1

To a solution of 2,7-dimethyl-1H-imidazo[4,5-b]pyridine (4.29 g) inchloroform (43 ml) was added m-chloroperbenzoic acid (80%, 7.55 g) atroom temperature and the mixture was refluxed under heating for 1 hr.After allowing to cool to room temperature, the reaction mixture wasdirectly purified by silica gel column chromatography(chloroform/methanol=9/1) and powdered with ethyl acetate to give2,7-dimethyl-1H-imidazo[4,5-b]pyridine-4-oxide as a brown powder (4.61g).

¹H-NMR(DMSO-d₆): 2.46(3H, s), 2.52(3H, s), 6.93(1H, d, J=5 Hz), 7.98(1H,d, J=5 Hz).

PREPARATION EXAMPLE 14-2

A mixture of 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-4-oxide (4.45 g),chloroform (4.5 ml) and phosphorus oxychloride (25.4 ml) was stirred at80° C. for 3 hr and concentrated to dryness under reduced pressure. Theresidue was poured into ice (75 g) and neutralized with aqueous ammoniaunder ice-cooling. After stirring at room temperature for 30 min, theprecipitated solid was collected by filtration and washed with water togive 5-chloro-2,7-dimethyl-3H-imidazo[4,5-b]pyridine as a gray powder(3.66 g).

¹H-NMR(DMSO-d₆): 2.49(3H, s), 2.52(3H, s), 7.08(1H, s).

PREPARATION EXAMPLE 14-3

In the same manner as in Preparation Example 16-3 to be mentioned later,methyl 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate was obtainedas colorless crystals (264 mg, 46.7%) from5-chloro-2,7-dimethyl-3H-imidazo[4,5-b]pyridine (500 mg).

¹H-NMR(DMSO-d₆): 2.56(6H, s), 3.87(3H, s), 7.78(1H, s). MASS(ESI): m/z206(M+1).

PREPARATION EXAMPLE 14-4

A mixture of methyl 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(2.70 g), 4-acetoxy-2-chlorobenzylbromide (4.85 g), potassium carbonate(2.73 g) and N,N-dimethylformamide (27 ml) was stirred at roomtemperature for 5 hr and left standing overnight. The reaction mixturewas partitioned between ethyl acetate and saturated brine, and theresulting precipitate was collected by filtration and washed with waterand ethyl acetate to give methyl3-(4-acetoxy-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(6.0 g) as a pale-brown powder. The mother liquor and washing werecombined and the organic layer was separated, dried over magnesiumsulfate and concentrated to dryness under reduced pressure. The residuewas powdered from diethyl ether to give the second lot (680 mg) as apale-brown powder.

¹H-NMR(CDCl₃): 2.24(3H, s), 2.53(3H, s), 2.63(3H, s), 3.84(3H, s),5.56(2H, s), 6.58(1H, d, J=8 Hz), 7.01(1H, dd, J=8, 2 Hz), 7.46(1H, d,J=2 Hz), 7.88(1H, s). MASS(ESI): m/z 388(M+1).

PREPARATION EXAMPLE 14-5

A mixture of methyl3-(4-acetoxy-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(6.5 g), conc. sulfuric acid (3.0 ml) and methanol (60 ml) was refluxedunder heating for 1.5 hr. The reaction mixture was diluted withchloroform (60 ml) and saturated aqueous sodium hydrogen carbonatesolution was gradually added under ice-cooling. The organic layer wasseparated, dried over magnesium sulfate, and concentrated to drynessunder reduced pressure. The residue was washed with diethyl ether togive methyl3-(2-chloro-4-hydroxybenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(3.81 g) as a pale-yellow powder.

¹H-NMR(CDCl₃): 2.49(3H, s), 2.62(3H, s), 3.86(3H, s), 5.46(2H, s),6.44(1H, d, J=8 Hz), 6.64(1H, dd, J=8, 2 Hz), 6.91(1H, d, J=2 Hz),7.88(1H, s), 9.99(1H, br s). MASS(ESI): m/z 346(M+1).

PREPARATION EXAMPLE 14-6

A mixture of methyl3-(2-chloro-4-hydroxybenzyl)-2,7-dimethylimidazo[4,5-b]pyridine-5-carboxylate(500 mg), 1-iodopropane (295 mg), potassium carbonate (300 mg) andN,N-dimethylformamide (5.0 ml) was stirred at 60° C. for 3 hr. Thereaction mixture was partitioned between ethyl acetate and water, andthe organic layer was washed twice with water and once with saturatedbrine, dried over magnesium sulfate, and concentrated to dryness underreduced pressure. The residue was powdered from diethyl ether to givemethyl3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethylimidazo[4,5-b]pyridine-5-carboxylate(490 mg) as a pale-yellow powder.

¹H-NMR(CDCl₃): 1.01(3H, t, J=6 Hz), 1.78(2H, m), 2.53(3H, s), 2.73(3H,s), 3.86(2H, t, J=6 Hz), 3.99(3H, s), 5.59(2H, s), 6.58(1H, d, J=8 Hz),6.64(1H, dd, J=8, 2 Hz), 6.96(1H, d, J=2 Hz), 7.97(1H,s). MASS(ESI): m/z388(M+1).

PREPARATION EXAMPLE 14-7

To a suspension of methyl3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(475 mg) in 1,4-dioxane was added 1N aqueous sodium hydroxide solution,and the mixture was heated to 60° C. and stirred for 30 min. It was aircooled and adjusted to pH 4 by dropwise addition of 1N hydrochloricacid. Water (25 ml) was added and the mixture was stirred at roomtemperature. The precipitated crystals were collected by filtration anddried under reduced pressure at 60° C. Thereto was added acetonitrile (3ml) and the mixture was heated and stirred at room temperature. Thecrystals were collected by filtration and dried under reduced pressureat 60° C. to give3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid as thin yellow crystals (426 mg).

¹H-NMR(CDCl₃): 1.02(3H, t, J=7 Hz), 1.71-1.85(2H, m), 2.62(3H, s),2.75(3H, s), 3.88(2H, t, J=7 Hz), 5.50(2H, s), 6.61(1H, d, J=8 Hz),6.68(1H, dd, J=1, 8 Hz), 6.99(1H, d, J=1 Hz), 8.03(1H, s). MASS(ESI):m/z 374(M+1).

PREPARATION EXAMPLE 15-1

In the same manner as in Preparation Example 14-6, methyl3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as a pale-yellow solid (1.17 g) from methyl3-[2-chloro-4-hydroxybenzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(1.05 g) and 1-iodopentane (662 mg).

¹H-NMR(CDCl₃): 0.92(3H, t, J=7 Hz), 1.30-1.47(4H, m), 1.69-1.81(2H, 30m), 2.53(3H, s), 2.72(3H, s), 3.89(2H, t, J=7 Hz), 3.99(3H, s), 5.59(2H,s), 6.56-6.67(2H, m), 6.96(1H, d, J=1 Hz), 7.26(1H, s), 7.97(1H, s).MASS(ESI): m/z 416(M+1).

PREPARATION EXAMPLE 15-2

In the same manner as in Preparation Example 14-7,3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (1.02 g) from methyl3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(1.15 g).

¹H-NMR(DMSO-d₆): 0.87(3H, t, J=7 Hz), 1.24-1.43(4H, m), 1.62-1.74(2H,m), 2.49(3H, s), 2.62(3H, s), 3.94(2H, t, J=7 Hz), 5.52(2H, s), 6.50(1H,d, J=8 Hz), 6.80(1H, dd, J=8, 2 Hz), 7.13(1H, d, J=2 Hz), 7.86(1H, s).MASS(ESI): m/z 400(M−1).

PREPARATION EXAMPLE 16-1

To a suspension of 2-amino-6-bromo-3-nitropyridine (21.8 g) in ethanol(220 ml)-water (22 ml) was added iron powder (39.0 g) at roomtemperature. Conc. hydrochloric acid (0.8 ml) was added and the mixturewas gradually heated with stirring to start the reaction. The mixturewas refluxed under heating for 2 hr, and an insoluble matter was removedby filtration while hot. The solvent was evaporated under reducedpressure, and water (200 ml) and active charcoal were added to theresulting solid, which was followed by heating. The insoluble matter wasremoved by filtration while hot, and water was evaporated under reducedpressure from the filtrate to give 2,3-diamino-6-bromopyridine (9.00 g)as a green brown powder. To the resulting solid from the above reactionwere added ethanol (100 ml)-water (100 ml) and the mixture was heatedfor dissolution. The insoluble matter was removed by filtration. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane/ethyl acetate=1/3)to further give the objective compound (8.25 g) as a black powder.

¹H-NMR(DMSO-d₆): 4.78(2H, br s), 5.80(2H, br s), 6.47(1H, d, J=8 Hz),6.61(1H, d, J=8 Hz). MASS(ESI): m/e 188,190(M+H)⁺.

PREPARATION EXAMPLE 16-2

2,3-Diamino-6-bromopyridine (8.16 g) and triethyl orthoacetate (12.0 ml)were mixed in acetic acid (41 ml), and the mixture was refluxed underheating for 29 hr. After allowing to cool, the solvent was evaporatedunder reduced pressure to give a crude product (10 g). This wasdissolved in a sufficient amount of dichloromethane and anhydrouspotassium carbonate and active charcoal were added. The mixture wasstirred at room temperature. The insoluble matter was removed byfiltration and the solvent was evaporated to give5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (7.59 g) as a pale-yellowpowder.

¹H-NMR(DMSO-d₆): 2.51(3H, s), 7.31(1H, d, J=8 Hz), 7.82(1H, d, J=8Hz).MASS(ESI): m/e 212,214(M+H)⁺.

PREPARATION EXAMPLE 16-3

Palladium acetate (1.18 g), 1,3-bis(diphenylphosphino)-propane (2.31 g)and 5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (3.72 g) were charged inan autoclave, and N,N-dimethylformamide (18.6 ml), methanol (14.9 ml)and triethylamine (5.4 ml) were added. The mixture was stirred at 85° C.for 14 hr in a 10 atm. carbon monoxide atmosphere. The reaction mixturewas allowed to cool and the solvent was evaporated. Methanol (60 ml) wasadded to the residue and heated, and the insoluble matter was filteredoff while hot. The filtrate was concentrated to give methyl2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (2.95 g) as a whitepowder.

¹H-NMR(CDCl₃): 2.82(3H, s), 4.05(3H, s), 8.04(1H, d, J=8 Hz), 8.10(1H,d, J=8 Hz). MASS(ESI): m/e 192(M+H)⁺.

PREPARATION EXAMPLE 16-4

3-Chloro-4-methylaniline (100.0 g) was dissolved in tetrahydrofuran (500ml) and di-tert-butyl dicarbonate (200.0 g) was added. The mixture wasrefluxed under heating for 3 hr. The reaction mixture was concentratedunder reduced pressure, and the residue was dissolved in ethyl acetate(1300 ml) and washed successively with 10% aqueous citric acid solution(500 ml), saturated aqueous sodium hydrogen carbonate solution (500 ml)and saturated brine (500 ml). The organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. To theresidue was added hexane (300 ml) and the precipitated crystals werecollected by filtration to giveN-(tert-butoxycarbonyl)-3-chloro-4-methylaniline (150.4 g) as colorlesscrystals.

¹H-NMR(CDCl₃): 1.53(9H, s), 2.31(3H, s), 6.40(1H, s), 7.05-7.13(2H, m),7.48(1H, s).

PREPARATION EXAMPLE 16-5

N-(tert-Butoxycarbonyl)-3-chloro-4-methylaniline (60.0 g) was dissolvedin N,N-dimethylformamide (300 ml) and 60% sodium hydride (10.4 g) wasgradually added under ice-cooling over 10 min. The reaction mixture wasstirred at room temperature for 30 min and methyl iodide (38.8 g) wasadded dropwise over 15 min under ice-cooling. The reaction mixture wasstirred at room temperature for 2 hr and concentrated under reducedpressure. Water (500 ml) was added and the mixture was extracted withethyl acetate (500 ml). The organic layer was washed successively withwater (500 ml), saturated aqueous sodium hydrogen carbonate solution(500 ml) and saturated brine (500 ml). The organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography and elutedwith hexane:ethyl acetate=9:1. The objective fraction was concentratedunder reduced pressure to giveN-(tert-butoxycarbonyl)-3-chloro-N,4-dimethylaniline as a pale-yellowoil (62.7 g). ¹H-NMR(CDCl₃): 1.46(9H, s), 2.34(3H, s), 3.26(3H, s),7.04(1H, dd, J=8, 2 Hz), 7.16(1H, d, J=8 Hz), 7.24(1H, d, J=2 Hz).

PREPARATION EXAMPLE 16-6

N-(tert-Butoxycarbonyl)-3-chloro-N,4-dimethylaniline (62.6 g) wasdissolved in carbon tetrachloride (310 ml), and N-bromosuccinimide (52.3g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (3.77 g) wereadded. The mixture was stirred at 55° C. for 2 hr and 75° C. for 1 hr,and hexane (500 ml) was added. The mixture was stirred under ice-coolingfor 1 hr. The reaction mixture was filtrated, and the filtrate wasconcentrated under reduced pressure. The residue was diluted with ethylacetate (310 ml) and washed successively with saturated aqueous sodiumhydrogen carbonate solution (500 ml) and saturated brine (500 ml). Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give4-bromomethyl-N-(tert-butoxycarbonyl)-N-methyl-3-chloroaniline as abrown oil (75.6 g).

¹H-NMR(CDCl₃): 1.48(9H, s), 3.25(3H, s), 4.57(2H, s), 7.17(1H, dd, J=8,2 Hz), 7.33(1H, d, J=2 Hz), 7.38(1H, d, J=8 Hz).

PREPARATION EXAMPLE 16-7

In the same manner as in Preparation Example 18-4 to be mentioned later,methyl3-(4-(N-(t-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(7.14 g) was obtained as colorless crystals and methyl1-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate(8.0 g) as a pale-brown powder, from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (10.0 g) and4-bromomethyl-N-(tert-butoxycarbonyl)-N-methyl-3-chloroaniline (23.6 g).

methyl3-(4-(N-(t-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 1.45(9H, s), 2.55(3H, s), 3.22(3H, s), 4.00(3H, s),5.65(2H, s), 6.58(1H, d, J=8 Hz), 7.00(1H, dd, J=8, 2 Hz), 7.39(1H, d,J=2 Hz), 8.06(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz).

methyl1-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 1.47(9H, s), 2.67(3H, s), 3.24(3H, s), 4.03(3H, s),5.42(2H, s), 6.45(1H, d, J=8 Hz), 7.03(1H, dd, J=8, 2 Hz), 7.45(1H, d,J=2 Hz), 7.55(1H, d, J=8 Hz), 8.06(1H, d, J=8 Hz).

PREPARATION EXAMPLE 16-8

In the same manner as in Preparation Example 14-7,3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (7.14 g) was obtained as a colorless powder from methyl3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(10.0 g).

¹H-NMR(CDCl₃): 1.47(9H, s), 2.64(3H, s), 3.24(3H, s), 5.57(2H, s),6.59(1H, d, J=8 Hz), 7.06(1H, dd, J=8, 2 Hz), 7.43(1H, d, J=2 Hz),8.17(1H, d, J=8 Hz), 8.23(1H, d, J=8 Hz).

PREPARATION EXAMPLE 17-1

Methyl3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(234 mg) was dissolved in dichloromethane (3 ml) and 4N hydrochloricacid (ethyl acetate solution) (2 ml) was added. The mixture was stirredat room temperature for 1 hr. The reaction mixture was concentratedunder reduced pressure and ethyl acetate was added. The precipitatedcrystals were collected by filtration and concentrated under reducedpressure with heating to give methyl3-(2-chloro-4-(methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatedihydrochloride (215 mg) as pale-red crystals.

¹H-NMR(DMSO-d₆): 2.67(3H, s), 3.91(3H, s), 5.56(2H, s), 6.56(1H, dd,J=8, 2 Hz), 6.78-6.82(2H, m), 8.15(1H, d, J=8 Hz), 8.31(1H, d, J=8 Hz).

PREPARATION EXAMPLE 17-2

Methyl3-(2-chloro-4-(methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatedihydrochloride (169 mg) was suspended in methanol (2 ml) andvaleraldehyde (70 mg) and sodium cyanoborohydride (51 mg) were added.The mixture was stirred at room temperature for 4 hr. To the reactionmixture was added 1N hydrochloric acid and the mixture was stirred for 1hr. Saturated aqueous sodium hydrogen carbonate solution was added toneutralize the solution and the mixture was extracted with ethylacetate. The organic layer was washed successively with saturatedaqueous sodium hydrogen carbonate solution and saturated brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyand eluted with chloroform:methanol=100:1. The objective fraction wasconcentrated under reduced pressure to give methyl3-(2-chloro-4-(methyl-(1-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(179 mg) as a pale-yellow oil.

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.20-1.42(4H, m), 1.46-1.57(2H, m),2.56(3H, s), 2.88(3H, s), 3.23(2H, t, J=7 Hz), 4.00(3H, s), 5.59(2H, s),6.39(1H, dd, J=8, 2 Hz), 6.62-6.67(2H, m), 8.04(1H, d, J=8 Hz), 8.13(1H,d, J=8 Hz).

PREPARATION EXAMPLE 17-3

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-(methyl-(1-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as a pale-yellow powder (180 mg) from methyl3-(2-chloro-4-(methyl-(1-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(150 mg).

¹H-NMR(CDCl₃): 0.88(3H, t, J=7 Hz), 1.22-1.55(6H, m), 2.61(3H, s),2.87(3H, s), 3.22(2H, br s), 5.48(2H, s), 6.40(1H, br s), 6.62(2H, brs), 8.10(2H, br s).

PREPARATION EXAMPLE 18-1

To a solution of 3-chloro-4-methylaniline (7.08 g) in methanol (35 ml)were added cyclohexanecarbaldehyde (5.33 g) and sodium cyanoborohydride(3.78 g) under ice-cooling and the mixture was stirred at roomtemperature. After one hour, the reaction mixture was concentrated andwater and saturated brine were added. The mixture was extracted 3 timeswith ethyl acetate. The organic layers were combined, washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by column chromatography(silica gel, hexane/ethyl acetate=15/1) to give3-chloro-N-cyclohexylmethyl-4-methylaniline as a pale-yellow oil (9.64g).

¹H-NMR(CDCl₃): 0.86-1.35(5H, m), 1.45-1.89(6H, m), 2.23(3H, s), 2.90(2H,d, J=7 Hz), 3.63(1H, br s), 6.40(1H, dd, J=8 and 2 Hz), 6.59(1H, d, J=2Hz), 6.97(1H, d, J=8 Hz). MASS(ESI): m/e 238(M+H)⁺.

PREPARATION EXAMPLE 18-2

In the same manner as in Preparation Example 16-4,N-(tert-butoxycarbonyl)-3-chloro-N-cyclohexylmethyl-4-methylaniline(13.68 g) was obtained as a pale-yellow oil from3-chloro-N-cyclohexylmethyl-4-methylaniline (9.63 g) and di-tert-butyldicarbonate (9.74 g).

¹H-NMR(CDCl₃): 0.82-1.27(5H, m), 1.34-1.78(6H, m), 1.43(9H, s), 2.35(3H,s), 3.46(2H, d, J=7 Hz), 6.99(1H, d, J=8 Hz), 7.17(1H, d, J=8 Hz),7.19(1H, s).

PREPARATION EXAMPLE 18-3

In the same manner as in Preparation Example 16-6,4-bromomethyl-N-(tert-butoxycarbonyl)-3-chloro-N-(cyclohexylmethyl)anilinewas obtained as a pale-yellow oil (16.83 g) fromN-(tert-butoxycarbonyl)-3-chloro-N-cyclohexylmethyl-4-methylaniline(13.60 g).

¹H-NMR(CDCl₃): 0.80-1.77(11H, m), 1.44(9H, s), 3.49(2H, d, J=7 Hz),4.58(2H,s), 7.10(1H, dd, J=8 and 2 Hz), 7.27(1H, d, J=2 Hz), 7.38(1H, d,J=8 Hz).

PREPARATION EXAMPLE 18-4

To a suspension of methyl 2-methylimidazo[4,5-b]pyridine-5-carboxylate(954 mg) in N,N-dimethylformamide (9.6 ml) was added sodium hydride (in70% mineral oil, 203 mg) under ice-cooling, and the mixture was stirredfor 30 min. To this reaction mixture was added4-bromomethyl-N-(tert-butoxycarbonyl)-3-chloro-N-(cyclohexylmethyl)aniline(2.70 g) and the mixture was stirred overnight at room temperature. Thereaction mixture was poured into water and the resulting product wasextracted twice with ethyl acetate. The organic layers were combined,washed successively with water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated and two kinds ofisomers—methyl3-(4-(N-(tert-butoxycarbonyl)-N-(cyclohexylmethyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(495 mg) and methyl1-(4-(N-(tert-butoxycarbonyl)-N-(cyclohexylmethyl)amino)-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate(827 mg)—were separated by silica gel column chromatography(chloroform/ethyl acetate=2/1) as white or pale-yellow powders.

methyl3-(4-(N-(tert-butoxycarbonyl)-N-(cyclohexylmethyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 0.77-1.76(11H, m), 1.43(9H, s), 2.54(3H, s), 3.46(2H, d,J=7 Hz), 4.00(3H, s), 5.66(2H, s), 6.59(1H, d, J=8 Hz), 6.95(1H, dd, J=8and 2 Hz), 7.33(1H, d, J=2 Hz), 8.07(1H, d, J=8 Hz), 8.15(1H, d, J=8Hz). MASS(ESI): m/e 527(M+H)⁺.

methyl1-(4-(N-(tert-butoxycarbonyl)-N-(cyclohexylmethyl)amino)-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 0.80-1.78(11H, m), 1.43(9H, s), 2.66(3H, s), 3.47(2H, d,J=7 Hz), 4.03(3H, s), 5.42(2H, s), 6.45(1H, d, J=8 Hz), 6.99(1H, dd, J=8and 2 Hz), 7.38(1H, d, J=2 Hz), 7.57(1H, d, J=8 Hz), 8.08(1H, d, J=8Hz). MASS(ESI): m/e 527(M+H)⁺.

PREPARATION EXAMPLE 18-5

In the same manner as in Example 42 to be mentioned later, methyl3-(2-chloro-4-(N-(cyclohexylmethyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(260 mg) was obtained as a white powder from methyl3-(4-(N-(tert-butoxycarbonyl)-N-(cyclohexylmethyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(384 mg).

¹H-NMR(CDCl₃): 0.82-1.90(11H, m), 2.55(3H, s), 2.89(2H, d, J=7 Hz),4.00(3H, s), 5.57(2H, s), 6.30(1H, dd, J=8 and 2 Hz), 6.58(1H, d, J=8Hz), 6.60(1H, d, J=2 Hz), 8.04(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz).MASS(ESI): m/e 427(M+H)⁺.

PREPARATION EXAMPLE 18-6

In the same manner as in Preparation Example 17-2, methyl3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(230 mg) was obtained as a white powder from methyl3-(2-chloro-4-(N-(cyclohexylmethyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(255 mg).

¹H-NMR(CDCl₃): 0.80-1.32(6H, m), 1.52-1.80(5H, m), 2.56(3H, s), 2.90(3H,s), 3.06(2H, d, J=7 Hz), 4.00(3H, s), 5.58(2H, s), 6.37(1H, dd, J=9 and2 Hz), 6.63(1H, d, J=9 Hz), 6.63(1H, d, J=2 Hz), 8.03(1H, d, J=8 Hz),8.12(1H, d, J=8 Hz). MASS(ESI): m/e 441(M+H)⁺.

PREPARATION EXAMPLE 18-7

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (219 mg) was obtained as a white powder from methyl3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(221 mg).

¹H-NMR(CDCl₃): 0.80-1.30(6H, m), 1.46-1.82(5H, m), 2.66(3H, s), 2.92(3H,s), 3.08(2H, d, J=7 Hz), 5.49(2H, s), 6.41(1H, dd, J=9 and 2 Hz),6.65(1H, d, J=2 Hz), 6.67(1H, d, J=9 Hz), 8.13(1H, d, J=8 Hz), 8.19(1H,d, J=8 Hz). MASS(ESI): m/e 425(M−H)⁻.

PREPARATION EXAMPLE 19-1

To a solution of 4-bromo-2-chlorobenzyl alcohol (3.56 g) and anhydroustriethylamine (3 ml) in anhydrous dichloromethane (36 ml) was addeddropwise methanesulfonyl chloride (1.4 ml) under a nitrogen flow underice-cooling. The mixture was stirred for 1 hr and the reaction mixturewas washed with water, saturated aqueous sodium hydrogen carbonatesolution and saturated brine, and dried over anhydrous magnesiumsulfate. The filtrate was concentrated to give4-bromo-2-chloro-1-(methanesulfonyloxymethyl)benzene as a pale-brownsolid (4.77 g).

¹H-NMR(CDCl₃): 3.03(3H, s), 5.29(2H, s), 7.37(1H, d, J=8 Hz), 7.47(1H,dd, J=8, 1 Hz), 7.60(1H, d, J=1 Hz). MASS(ESI): m/e 298(M−1).

PREPARATION EXAMPLE 19-2

In the same manner as in Preparation Example 4-5, methyl3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as colorless crystals (950 mg) from methyl2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (550 mg) and4-bromo-2-chloro-1-(methanesulfonyloxymethyl)benzene (963 mg).

¹H-NMR(CDCl₃): 2.52(3H, s), 2.73(3H, s), 3.98(3H, s), 5.59(2H, s),6.49(1H, d, J=8 Hz), 7.22(1H, d, J=8 Hz), 7.60(1H, s), 7.99(1H, d, J=8Hz).

PREPARATION EXAMPLE 19-3

In the same manner as in Preparation Example 14-7,3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (870 mg) from methyl3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(950 mg).

¹H-NMR(DMSO-d₆): 2.49(3H, s), 2.62(3H, s), 5.55(2H, s), 6.47(1H, d, J=8Hz), 7.34(1H, dd, J=8, 1 Hz), 7.85(1H, d, J=1 Hz).

PREPARATION EXAMPLE 20-1

In the same manner as in Preparation Example 18-4, methyl3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (399 mg) wasobtained as a pale-brown solid and methyl1-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate(245 mg) as a brown solid, from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (500 mg) and3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (662 mg).

methyl3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.56(3H, s), 3.97(3H, s), 5.84(2H, s), 7.98(1H, br s),8.06(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz), 8.51(1H, br s). MASS(ESI): m/z385(M+1).

methyl1-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.72(3H, s), 4.02(3H, s), 5.62(2H, s), 7.62(1H, d, J=8Hz), 8.01(1H, br s), 8.07(1H, d, J=8 Hz), 8.60(1H, br s). MASS(ESI): m/z385(M+1).

PREPARATION EXAMPLE 20-2

In the same manner as in Preparation Example 14-7,3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as a colorless solid (271 mg) from methyl3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(395 mg).

¹H-NMR(DMSO-d₆): 2.51(3H, s), 3.97(3H, s), 5.89(2H, s), 7.98(1H, br s),8.09(1H, d, J=8 Hz), 8.60(1H, d, J=1 Hz), 8.73(1H, br s). MASS(ESI): m/z369(M−1).

PREPARATION EXAMPLE 21-1

To a solution of6-bromo-2-[N-(2-chloro-4-phenylbenzyl)acetamido]-3-nitropyridine (15.4g) in dioxane (150 ml) was added 1N aqueous sodium hydroxide solution(43.5 ml) at room temperature and the mixture was heated to 50° C. Themixture was stirred for 3 hr, ice-cooled, and neutralized with 1Nhydrochloric acid. Water (300 ml) was added and the precipitatedcrystals were collected by filtration and dried under reduced pressureto give 6-bromo-2-[N-(2-chloro-4-phenylbenzyl)amino]-3-nitropyridine(13.8 g) as yellow crystals.

¹H-NMR(CDCl₃): 4.94(2H, d, J=5 Hz), 6.82(1H, d, J=8 Hz), 7.32-7.61(6H,m), 7.63(1H, d, J=1 Hz), 8.23(1H, d, J=8 Hz), 8.76(1H, br s).

PREPARATION EXAMPLE 21-2

To a solution of6-bromo-2-[N-(2-chloro-4-phenylbenzyl)-amino]-3-nitropyridine (13.5 g)in acetic acid (27 ml) and ethanol (81 ml) was added iron powder (7.2 g)at room temperature under a nitrogen flow, and the mixture was refluxedunder heating. After 2 hr, the reaction mixture was cooled, filteredthrough celite, and washed with ethyl acetate. The filtrate wasconcentrated and subjected to azeotropic distillation twice withtoluene. Ethyl acetate and saturated aqueous sodium hydrogen carbonatesolution were added to the residue and the mixture was stirred at roomtemperature for 10 min. This mixture was filtered through celite andwashed with ethyl acetate. The organic layer was separated, washed withsaturated brine and dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated and the residue was applied toflash silica gel column chromatography (silica gel, 400 ml) and elutedwith hexane:ethyl acetate=5:1-3:1-2:1 to give3-amino-6-bromo-2-[N-(2-chloro-4-phenylbenzyl)amino]pyridine (10.6 g) asa black gum.

¹H-NMR(CDCl₃): 3.14(2H, br s), 4.75(2H, s), 6.67(1H, d, J=8 Hz),6.73(1H, d, J=8 Hz), 7.33-7.49(4H, m), 7.51-7.64(4H, m). MASS(ESI): m/z388(M+1).

PREPARATION EXAMPLE 21-3

A mixture of3-amino-6-bromo-2-(N-(2-chloro-4-phenylbenzyl)amino)pyridine (1.85 g),tetraethoxymethane (4.3 g) and acetic acid (18.5 ml) was stirred at roomtemperature overnight and at 70° C. for 7 hr. The reaction mixture wasconcentrated to dryness under reduced pressure, and toluene was added,which was followed by concentration under reduced pressure. The residuewas dissolved in ethyl acetate and washed twice with saturated aqueoussodium hydrogen carbonate solution and once with saturated brine. Theorganic layer was dried over magnesium sulfate and concentrated todryness under reduced pressure. The residue was applied to silica gelcolumn (n-hexane:ethyl acetate=9:1) to give a single product (55 mg) of5-bromo-3-(2-chloro-4-phenylbenzyl)-2-ethoxy-3H-imidazo[4,5-b]pyridineand a mixture (977 mg) with a byproduct each as pale-brown amorphous.

¹H-NMR(CDCl₃): 1.43(3H, t, J=7 Hz), 4.60(2H, q, J=7 Hz), 5.41(2H, s),6.94(1H, d, J=8 Hz), 7.25-7.67(9H). MASS(ESI): m/z 444(M+H).

PREPARATION EXAMPLE 21-4

5-Bromo-3-(2-chloro-4-phenylbenzyl)-2-ethoxy-3H-imidazo[4,5-b]pyridine(57 mg) was dissolved in N,N-dimethylformamide (1.3 ml) and tert-butylalcohol (1.0 ml) and triethylamine (30.4 mg),1,3-bis(diphenylphosphino)propane (17 mg) and palladium (II) acetate(9.3 mg) were successively added. The mixture was stirred under a 10atm. carbon monoxide atmosphere at 85° C. for 48 hr. The insolublematter was filtered off and washed with chloroform. The filtrate andwashing were combined and concentrated to dryness under reducedpressure. The residue was purified by thin layer chromatography(chloroform:methanol=19:1) to give3-(2-chloro-4-phenylbenzyl)-2-ethoxy-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (43 mg) as a brown oil.

¹H-NMR(CDCl₃): 1.52(3H, t, J=7 Hz), 4.72(2H, q, J=7 Hz), 5.45(2H, s),7.07(1H, d, J=8 Hz), 7.33-7.72(7H), 7.92(1H, d, J=8 Hz), 8.13(1H, d, J=8Hz).

PREPARATION EXAMPLE 22-1

In the same manner as in Preparation Example 4-5, methyl3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as a colorless solid (487 mg) from methyl2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) and3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (370 mg).

¹H-NMR(CDCl₃): 2.55(3H, s), 2.74(3H, s), 3.96(3H, s), 5.82(2H, s),7.95(1H, br s), 7.98(1H, d, J=1 Hz), 8.51(1H, br s).

PREPARATION EXAMPLE 22-2

In the same manner as in Preparation Example 14-7,3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as a colorless solid (398 mg) from methyl3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(450 mg).

¹H-NMR(DMSO-d₆): 2.51(3H, s), 2.62(3H, s), 5.86(2H, s), 7.83(1H, br s),8.60(1H, br s), 8.74(1H, br s). MASS(ESI): m/z 383(M−1).

PREPARATION EXAMPLE 23-1

Lithium aluminum hydride (1.78 g) was suspended in dry tetrahydrofuran(10 ml), and 2,6-dichloronicotinic acid was added under ice-cooling atan inside temperature of not more than 10° C. The mixture was stirredunder ice-cooling for 1 hr and 28% aqueous ammonia was added dropwise tothe reaction mixture until foams disappeared. Methanol was added and themixture was stirred at room temperature for 3 hr, and filtered throughcelite. The mother liquor was concentrated and the residue was appliedto flash silica gel column chromatography (silica gel, 200 ml) andeluted with chloroform:ethyl acetate=8:1 to give2,6-dichloro-3-hydroxymethylpyridine as colorless crystals (2.89 g).

¹H-NMR(CDCl₃): 2.11(1H, t, J=7 Hz), 4.77(2H, d, J=7 Hz), 7.32(1H, d, J=8Hz), 7.87(1H, d, J=8 Hz). MASS(ESI): m/z 176(M−1).

PREPARATION EXAMPLE 23-2

In the same manner as in Preparation Example 19-1,2,6-dichloro-3-(methanesulfonyloxymethyl)pyridine was obtained as apale-brown oil (1.3 g) from 2,6-dichloro-3-hydroxymethylpyridine (900mg).

¹H-NMR(CDCl₃): 3.11(3H, s), 5.31(2H, s), 7.36(1H, d, J=8 Hz), 7.83(1H,d, J=8 Hz).

PREPARATION EXAMPLE 23-3

In the same manner as in Preparation Example 18-4, methyl3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as colorless crystals (684 mg), and methyl1-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylateas a brown solid (297 mg), from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (700 mg) and2,6-dichloro-3-(methanesulfonyloxymethyl)pyridine (1.03 g).

methyl3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.61(3H, s), 4.00(3H, s), 5.63(2H, s), 7.15(1H, d, J=8Hz), 7.18(1H, d, J=8 Hz), 8.07(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz).MASS(ESI): m/z 351(M+1).

methyl1-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.66(3H, s), 4.03(3H, s), 5.42(2H, s), 6.74(1H, d, J=8Hz), 7.19(1H, d, J=8 Hz), 7.56(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz).MASS(ESI): m/z 351(M+1).

PREPARATION EXAMPLE 23-4

In the same manner as in Preparation Example 14-7,3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as a colorless solid (578 mg) from methyl3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(665 mg).

¹H-NMR(DMSO-d₆): 2.56(3H, s), 5.60(2H, s), 7.23(1H, d, J=8 Hz), 7.46(1H,d, J=8 Hz), 8.01(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz). MASS(ESI): m/z335(M−1).

PREPARATION EXAMPLE 24-1

In the same manner as in Preparation Example 14-6,5-bromo-3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (886 mg) from5-bromo-3-(2-chloro-4-hydroxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine(790 mg) and (bromomethyl)cyclohexane (763 mg).

¹H-NMR(CDCl₃): 0.94-1.90(14H, m), 2.75(2H, q, J=7 Hz), 3.69(2H, d, J=7Hz), 5.49(2H, s), 6.53(1H, d, J=8 Hz), 6.65(1H, dd, J=1, 8 Hz), 6.95(1H,d, J=1 Hz), 7.37(1H, d, J=8 Hz), 7.87(1H, d, J=8 Hz). MS(ESI): m/z 462,464(M+1).

PREPARATION EXAMPLE 24-2

In the same manner as in Preparation Example 12-2, methyl3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-3H-imidazo-[4,5-b]pyridine-5-carboxylatewas obtained as pale-yellow crystals (549 mg) from5-bromo-3-(2-chloro-4-(cyclohexylmethyl-oxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine(760 mg).

¹H-NMR(CDCl₃): 0.94-1.34(6H, m), 1.38(3H, t, J=7 Hz), 1.65-1.87(5H, m),2.80(2H, q, J=7 Hz), 3.69(2H, d, J=7 Hz), 4.00(3H, s), 5.62(2H, s),6.58(1H, d, J=8 Hz), 6.62(1H, dd, J=1, 8 Hz), 6.95(1H, d, J=1 Hz),8.10(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz). MS(ESI): m/z 442(M+1).

PREPARATION EXAMPLE 24-3

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (453 mg) from methyl3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(532 mg).

¹H-NMR(CDCl₃): 0.94-1.38(6H, m), 1.44(3H, t, J=7 Hz), 1.64-1.88(5H, m),2.90(2H, q, J=7 Hz), 3.71(2H, d, J=7 Hz), 5.53(2H, s), 6.60(1H, d, J=8Hz), 6.67(1H, dd, J=1, 8 Hz), 7.00(1H, d, J=1 Hz), 8.16-8.24(2H, m).MS(ESI): m/z 426(M−1).

PREPARATION EXAMPLE 25-1

In the same manner as in Preparation Example 14-4, methyl3-(2-chloro-4-iodobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(163 mg) and methyl1-(2-chloro-4-iodobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate(108 mg) were obtained each as a pale-brown powder from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg) and2-chloro-4-iodobenzylbromide (780 mg).

methyl3-(2-chloro-4-iodobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.54(3H, s), 3.99(3H, s), 5.62(2H, s), 6.37(1H, d, J=8Hz), 7.43(1H, d, J=8 Hz), 7.80(1H, s), 8.08(1H, d, J=8 Hz), 8.16(1H, d,J=8 Hz).

methyl1-(2-chloro-4-iodobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.65(3H, s), 4.03(3H, s), 5.38(2H, s), 6.20(1H, d, J=8Hz), 7.48(1H, d, J=8 Hz), 7.53(1H, d, J=8 Hz), 7.83(1H, s), 8.09(1H, d,J=8 Hz).

PREPARATION EXAMPLE 25-2

To a suspension of tetrakis(triphenylphosphine)palladium(0) (262 mg) inN,N-dimethylformamide (20 ml) were added methyl3-(2-chloro-4-iodobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(2.00 g), furan-2-boric acid (608 mg) and potassium carbonate (1.88 g)at room temperature in a nitrogen atmosphere. After heating at 80° C.for 12 hr, the reaction mixture was ice-cooled and water was added. Theprecipitated powder was collected by filtration and washed with water.This powder was dried and applied to flash silica gel columnchromatography (silica gel, 150 ml) and eluted with chloroform:ethylacetate=10:1-5:1-3:1 to give a pale-brown solid (1.66 g). This wascrystallized from methanol to give methyl3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylateas colorless crystals (1.58 g).

¹H-NMR(CDCl₃): 2.55(3H, s), 4.00(3H, s), 5.69(2H, s), 6.47(1H, m),6.63-6.27(2H, m), 7.38(1H, dd, J=8, 1 Hz), 7.47(1H, d, J=1 Hz), 7.75(1H,d, J=1 Hz), 8.07(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz). MASS(ESI): m/z382(M+1).

PREPARATION EXAMPLE 25-3

In the same manner as in Preparation Example 14-7,3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless solid (1.44 g) from methyl3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(1.57 g).

¹H-NMR(DMSO-d₆): 2.55(3H, s), 4.00(3H, s), 5.69(2H, s), 6.47(1H, m),6.63-6.27(2H, m), 7.38(1H, dd, J=8, 1 Hz), 7.47(1H, d, J=1 Hz), 7.75(1H,d, J=1 Hz), 8.07(1H, d, J=1 Hz), 8.16(1H, d, J=1 Hz). MASS(ESI): m/z369(M−1).

PREPARATION EXAMPLE 26-1

In the same manner as in Preparation Example 16-5,N-(tert-butoxycarbonyl)-3-chloro-N-ethyl-4-methylaniline (11.8 g) wasobtained as a pale-yellow oil fromN-(tert-butoxycarbonyl)-3-chloro-4-methylaniline (10.0 g) and ethyliodide (7.10 g).

¹H-NMR(CDCl₃): 1.13(3H, t, J=7 Hz), 1.44(9H, s), 2.35(3H, s), 3.64(2H,q, J=7 Hz), 6.98(1H, dd, J=8, 2 Hz), 7.16-7.20(2H, m).

PREPARATION EXAMPLE 26-2

In the same manner as in Preparation Example 16-6,4-bromomethyl-N-(tert-butoxycarbonyl)-3-chloro-N-ethylaniline (14.1 g)was obtained as a brown oil fromN-(tert-butoxycarbonyl)-3-chloro-N-ethyl-4-methylaniline (11.7 g). Thissubstance was used in the next reaction without further purification.

PREPARATION EXAMPLE 26-3

In the same manner as in Preparation Example 14-4, methyl3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(534 mg) was obtained as pale-orange crystals, and methyl1-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate(701 mg) as a pale-orange powder, from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (950 mg) and4-bromomethyl-N-(tert-butoxycarbonyl)-3-chloro-N-ethylaniline (2.25 g).

methyl3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 1.13(3H, t, J=7 Hz), 1.44(9H, s), 2.54(3H, s), 3.63(3H,q, J=7 Hz), 4.00(3H, s), 5.66(2H, s), 6.60(1H, d, J=8 Hz), 6.95(1H, dd,J=8, 2 Hz), 7.34(1H, d, J=2 Hz), 8.07(1H, d, J=8 Hz), 8.15(1H, d, J=8Hz).

methyl1-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 1.14(3H, t, J=7 Hz), 1.44(9H, s), 2.66(3H, s), 3.64(2H,q, J=7 Hz), 4.02(3H, s), 5.42(2H, s), 6.45(1H, d, J=8 Hz), 6.99(1H, dd,J=8, 2 Hz), 7.39(1H, d, J=2 Hz), 7.56(1H, d, J=8 Hz), 8.07(1H, d, J=8Hz).

PREPARATION EXAMPLE 26-4

In the same manner as in Preparation Example 14-7,3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (535 mg) was obtained as a pale-yellow powder from methyl3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(514 mg).

¹H-NMR(DMSO-d₆): 1.03(3H, t, J=7 Hz), 1.37(9H, s), 2.52(3H, s), 3.59(2H,q, J=7 Hz), 5.61(2H, s), 6.55(1H, d, J=8 Hz), 7.11(1H, dd, J=8, 2 Hz),7.49(1H, d, J=2 Hz), 8.01(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz).

PREPARATION EXAMPLE 27-1

In the same manner as in Preparation Example 4-5, methyl3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(1.26 g) was obtained as a pale-yellow powder from methyl2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (800 mg) and4-bromomethyl-N-(tert-butoxycarbonyl)-3-chloro-N-methylaniline (1.96 g).

¹H-NMR(CDCl₃): 1.45(9H, s), 2.54(3H, s), 2.73(3H, s), 3.21(3H, s),3.99(3H, s), 5.63(2H, s), 6.55(1H, d, J=8 Hz), 6.98(1H, dd, J=8, 2 Hz),7.39(1H, d, J=2 Hz), 7.97(1H, s). MASS(ESI): m/z 459(M+H)⁺.

PREPARATION EXAMPLE 27-2

In the same manner as in Preparation Example 14-7,3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (805 mg) was obtained as a pale-yellow powder from methyl3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(900 mg).

¹H-NMR(DMSO-d₆): 1.38(9H, s), 2.51(3H, s), 2.63(3H, s), 3.15(3H, s),5.57(2H, s), 6.50(1H, d, J=8 Hz), 7.15(1H, dd, J=8, 2 Hz), 7.55(1H, d,J=2 Hz), 7.87(1H, s). MASS(ESI): m/z 443(M−H)⁻.

PREPARATION EXAMPLE 28-1

In the same manner as in Preparation Example 4-5, methyl3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(846 mg) was obtained as a brown oil from methyl2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (400 mg) and4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl bromide (816mg).

¹H-NMR(CDCl₃): 1.13(3H, t, J=6 Hz), 1.44(9H, s), 2.54(3H, s), 2.74(3H,s), 3.62(2H, q, J=6 Hz), 3.99(3H, s), 5.64(2H, s), 6.55(1H, d, J=8 Hz),6.94(1H, dd, J=8, 2 Hz), 7.34(1H, d, J=2 Hz), 7.97(1H, s).

PREPARATION EXAMPLE 28-2

In the same manner as in Preparation Example 14-7,3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (658 mg) was obtained as a brown powder from methyl3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(828 mg).

¹H-NMR(CDCl₃): 1.15(3H, t, J=6 Hz), 1.44(9H, s), 2.62(3H, s), 2.76(3H,s), 3.65(2H, q, J=6 Hz), 5.55(2H, s), 6.56(1H, d, J=8 Hz), 7.00(1H, dd,J=8, 2 Hz), 7.39(1H, d, J=2 Hz), 8.06(1H, s). MASS(ESI): m/z 459(M).

PREPARATION EXAMPLE 29-1

In the same manner as in Preparation Example 19-1,2-chloro-1-methanesulfonyloxymethyl-4-nitrobenzene (3.56 g) was obtainedas brown crystals from 2-chloro-4-nitrobenzyl alcohol (2.5 g) andmethanesulfonyl chloride (1.68 g).

¹H-NMR(CDCl₃): 3.12(3H, s), 5.40(2H, s), 7.73(1H, d, J=8 Hz), 8.18(1H,dd, J=2,8 Hz), 8.79(1H, s).

PREPARATION EXAMPLE 29-2

In the same manner as in Preparation Example 18-4, methyl3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(1.02 g) was obtained as white crystals, and methyl1-(2-chloro-4-nitrobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate(330 mg) as pale-brown crystals, from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (2.00 g) and2-chloro-1-methanesulfonyloxymethyl-4-nitrobenzene (3.06 g).

methyl3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.55(3H, s), 3.99(3H, s), 5.73(2H, s), 6.80(1H, d, J=8Hz), 7.97(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz),8.33(1H, s).

methyl1-(2-chloro-4-nitrobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.65(3H, s), 4.03(3H, s), 5.51(2H, s), 6.62(1H, d, J=8Hz), 7.53(1H, d, J=8 Hz), 8.01(1H, dd, J=2,8 Hz), 8.10(1H, d, J=8 Hz),8.39(1H, d, J=2 Hz).

PREPARATION EXAMPLE 29-3

Methyl3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(705 mg) was suspended in ethanol (6 ml) and reduced iron (655 mg) andacetic acid (2.11 ml) were added, which was followed by refluxing underheating for 3 hr. The reaction mixture was filtered through celite, andthe filtrate was concentrated under reduced pressure. To the residue wasadded saturated aqueous sodium hydrogen carbonate solution to make theresidue alkaline and extracted with ethyl acetate. The organic layer waswashed successively with saturated aqueous sodium hydrogen carbonatesolution and saturated brine, dried over anhydrous magnesium sulfate andfiltrated. The filtrate was concentrated under reduced pressure to givemethyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(608 mg) as a white powder.

¹H-NMR(CDCl₃): 2.53(3H, s), 3.75(2H, s), 4.00(3H, s), 5.67(2H, s),6.40(1H, dd, J=2,8 Hz), 6.54(1H, dd, J=1,8 Hz), 6.72(1H, d, J=1 Hz),8.02(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz).

PREPARATION EXAMPLE 29-4

Methyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(1.00 g) was dissolved in acetic acid (5.0 ml) and2,5-dimethoxytetrahydrofuran (420 mg) was added, which was followed byrefluxing under heating for 2 hr. The reaction mixture was concentratedunder reduced pressure and the residue was applied to silica gel columnchromatography and eluted with chloroform:ethyl acetate=3:1. Theobjective fraction was concentrated under reduced pressure and ethylacetate (10.0 ml) was added to the residue. After heating, the mixturewas allowed to cool and the precipitated crystals were collected byfiltration to give methyl3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(641 mg) as colorless crystals.

¹H-NMR(CDCl₃): 2.58(3H, s), 4.00(3H, s), 5.69(2H, s), 6.34(2H, t, J=2Hz), 6.74(1H, d, J=8 Hz), 7.03(2H, t, J=2 Hz), 7.14(1H, dd, J=8, 2 Hz),7.49(1H, d, J=2 Hz), 8.08(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz).MASS(ESI): m/z 381(M+H)⁺.

PREPARATION EXAMPLE 29-5

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid(426 mg) was obtained as a pale-yellow powder from methyl3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(450 mg).

¹H-NMR(DMSO-d₆): 2.55(3H, s), 5.63(2H, s), 6.26(2H, t, J=2 Hz), 6.67(1H,d, J=8 Hz), 7.41(2H, t, J=2 Hz), 7.47(1H, dd, J=8, 2 Hz), 7.87(1H, d,J=2 Hz), 8.02(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz). MASS(ESI): m/z365(M−H)⁻.

PREPARATION EXAMPLE 30-1

In the same manner as in Preparation Example 14-4, methyl3-(2-chloro-4-iodobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(6.42 g) was obtained as a white powder from methyl2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (3.00 g) and2-chloro-4-iodobenzyl bromide (7.00 g).

¹H-NMR(DMSO-d₆): 2.51(3H, s), 2.63(3H, s), 3.85(3H, s), 5.50(2H, s),6.30(1H, d, J=8 Hz), 7.58(1H, d, J=8 Hz), 7.88(1H, s), 7.95(1H, s).

PREPARATION EXAMPLE 30-2

In the same manner as in Preparation Example 25-2, methyl3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as colorless crystals (1.58 g) from methyl3-[(2-chloro-4-iodo)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(2.00 g) and furan-2-boric acid (608 mg).

¹H-NMR(CDCl₃): 2.54(3H, s), 2.74(3H, s), 3.99(3H, s), 5.66(2H, s),6.46(1H, m), 6.61(1H, d, J=8 Hz), 6.64(1H, d, J=5 Hz), 7.37(1H, dd, J=8,1 Hz), 7.46(1H, d, J=1 Hz), 7.74(1H, d, J=1 Hz), 7.98(1H, s). MASS(ESI):m/z 395(M+1).

PREPARATION EXAMPLE 30-3

In the same manner as in Preparation Example 14-7,3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as a colorless solid (1.07 g) from methyl3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(1.17 g).

¹H-NMR(DMSO-d₆): 2.52(3H, s), 2.64(3H, s), 5.61(2H, s), 6.56-6.63(2H,m), 7.06(1H, d, J=5 Hz), 7.54(1H, dd, J=8, 1 Hz), 7.77(1H, d, J=1 Hz),7.85-7.90(2H, m). MASS(ESI): m/z 380(M−1).

PREPARATION EXAMPLE 31-1

To a solution of 2,4-dichlorobenzaldehyde (3.5 g) in sulfuric acid (15ml) was added dropwise fuming nitric acid under ice-cooling at not morethan 10° C. over 15 min. The mixture was stirred under ice-cooling for 1hr and the reaction mixture was poured into ice (50 g). The aqueouslayer was extracted with ethyl acetate, and the organic layer was washedwith water and saturated brine. The organic layer was dried overanhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated to give pale-yellow crystals (4.39 g). This wasrecrystallized from isopropyl ether to give2,4-dichloro-5-nitrobenzaldehyde as pale-yellow crystals (3.50 g).

¹H-NMR(CDCl₃): 7.73(1H, s), 8.44(1H, s).

PREPARATION EXAMPLE 31-2

To a solution of 2,4-dichloro-5-nitrobenzaldehyde (2.0 g) in ethanol (20ml) was added sodium borohydride (688 mg) under ice-cooling. After 1 hr,water was added to the reaction mixture and extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated to give a pale-yellow solid (2.07 g). This wasapplied to flash silica gel column chromatography (silica gel, 80 ml)and eluted with hexane:ethyl acetate=10:1-5:1 to give2,4-dichloro-5-nitrobenzyl alcohol as pale-yellow crystals (1.97 g).

¹H-NMR(CDCl₃): 2.08(1H, t, J=5 Hz), 4.82(2H, d, J=5 Hz), 7.57(1H, s),8.15(1H, s).

PREPARATION EXAMPLE 31-3

In the same manner as in Preparation Example 19-1,2,4-dichloro-1-methanesulfonyloxymethyl-5-nitrobenzene was obtained as acolorless oil (2.75 g) from 2,4-dichloro-5-nitrobenzyl alcohol (1.96 g).

¹H-NMR(CDCl₃): 3.14(3H, s), 5.33(2H, s), 7.67(1H, s), 8.08(1H, s).

PREPARATION EXAMPLE 31-4

In the same manner as in Preparation Example 14-4, methyl3-[(2,4-dichloro-5-nitro)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as colorless crystals (2.19 g) and methyl1-[(2,4-dichloro-5-nitro)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylateas pale-yellow amorphous (473 mg), from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (1.69 g).

methyl3-[(2,4-dichloro-5-nitro)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.64(3H, s), 4.00(3H, s), 5.64(2H, s), 7.57(1H, s),6.68(1H, s), 8.08(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz). MASS(ESI): m/z395(M+1).

methyl1-[(2,4-dichloro-5-nitro)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.68(3H, s), 4.03(3H, s), 5.46(2H, s), 7.11(1H, s),7.54(1H, d, J=8 Hz), 7.73(1H, s), 8.11(1H, d, J=8 Hz). MASS(ESI): m/z395(M+1).

PREPARATION EXAMPLE 31-5

In the same manner as in Preparation Example 14-7,3-[(2,4-dichloro-5-nitro)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as a colorless solid (382 mg) from methyl3-[(2,4-dichloro-5-nitro)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(450 mg).

¹H-NMR(DMSO-d₆): 2.57(3H, s), 2.64(3H, s), 5.66(2H, s), 7.58(1H, s),8.00(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz), 8.16(1H, s). MASS(ESI): m/z381(M−1).

PREPARATION EXAMPLE 32-1

In the same manner as in Preparation Example 29-3, methyl3-[(5-amino-2,4-dichloro)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as colorless crystals (1.25 g) from methyl3-[(2,4-dichloro-5-nitro)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(1.5 g).

¹H-NMR(CDCl₃): 2.51(3H, s), 3.94(3H, s), 4.23(2H, br s), 5.47(2H, s),6.02(1H, s), 7.25(1H, s), 7.26(1H, s), 8.01(1H, d, J=8 Hz), 8.04(1H, d,J=8 Hz). MASS(ESI): m/z 365(M+1).

PREPARATION EXAMPLE 32-2

To a solution of methyl3-[(5-amino-2,4-dichloro)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(500 mg) in formic acid (5 ml) was added 37% formalin (1.03 ml) at roomtemperature and the mixture was refluxed under heating. After 30 min,the reaction mixture was concentrated and chloroform and saturatedaqueous sodium hydrogen carbonate solution were added to the residue.The organic layer was separated and the aqueous layer was extracted withchloroform. The organic layers were combined and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated andthe residue was applied to flash silica gel column chromatography(silica gel, 50 ml) and eluted with chloroform:ethyl acetate=5:1 to givemethyl3-[(2,4-dichloro-5-(N,N-dimethylamino))benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylateas a colorless solid (489 mg).

¹H-NMR(CDCl₃): 2.58(6H, s), 2.62(3H, s), 4.01(3H, s), 5.60(2H, s),6.70(1H, s), 7.41(1H, s), 8.06(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz).MASS(ESI): m/z 393(M+1).

PREPARATION EXAMPLE 32-3

In the same manner as in Preparation Example 14-7,3-[(2,4-dichloro-5-(N,N-dimethylamino))benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as a colorless solid (410 mg) from methyl3-[(2,4-dichloro-5-(N,N-dimethylamino))-benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(470 mg).

¹H-NMR(DMSO-d₆): 2.54(6H, s), 2.59(3H, s), 5.56(2H, s), 6.76(1H, s),7.60(1H, s), 8.00(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz). MASS(ESI): m/z377(M−1).

PREPARATION EXAMPLE 33-1

A mixture of methyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(300 mg), di-tert-butyl dicarbonate (476 mg), pyridine(143 mg),4-dimethylaminopyridine (22 mg) and tetrahydrofuran (1.5 ml) wasrefluxed under heating for 2 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith water and saturated brine, dried over magnesium sulfate, andconcentrated to dryness under reduced pressure. The residue was purifiedby silica gel column chromatography (eluted with chloroform) to givemethyl3-[4-(N,N-bis-(tert-butoxycarbonyl)-amino)-2-chlorobenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(420 mg) as a pale-yellow oil.

¹H-NMR(CDCl₃): 1.42(18H, s), 2.50(3H, s), 4.00(3H, s), 5.69(2H, s),6.64(1H, d, J=8 Hz), 6.92(1H, dd, J=8, 2 Hz), 7.29(1H, d, J=2 Hz),8.06(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz).

PREPARATION EXAMPLE 33-2

Methyl3-(4-(N,N-bis-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(391 mg) was dissolved in 1,4-dioxane (4 ml). 1N Aqueous sodiumhydroxide solution (3.7 ml) was added and the mixture was stirred atroom temperature for 2 days and at 80° C. for 2 hr. To the reactionmixture was added 1N hydrochloric acid to adjust the pH to 4. Water (40ml) was added and the precipitated crystals were collected by filtrationto give3-(4-(N-(tert-butoxycarbonyl)-amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (261 mg) as pale-yellow crystals.

¹H-NMR(DMSO-d₆): 1.46(9H, s), 2.50(3H, s), 5.54(2H, s), 6.57(1H, d, J=8Hz), 7.23(1H, dd, J=8, 2 Hz), 7.73(1H, d, J=2 Hz), 8.00(1H, d, J=8 Hz),8.12(1H, d, J=8 Hz), 9.61(1H, s).

PREPARATION EXAMPLE 34-1

In the same manner as in Example 65 to be mentioned later, methyl3-(2-chloro-4-(ethoxycarbonylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(315 mg) was obtained as a pale-yellow powder from methyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(300 mg).

¹H-NMR(CDCl₃): 1.29(3H, t, J=7 Hz), 2.53(3H, s), 3.99(3H, s), 4.21(2H,q, J=7 Hz), 5.60(2H, s), 6.53(1H, d, J=8 Hz), 6.97(1H, dd, J=8, 2 Hz),7.68(1H, d, J=2 Hz), 8.06(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz).MASS(ESI): m/z 403(M+1).

PREPARATION EXAMPLE 34-2

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-(ethoxycarbonylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (319 mg) was obtained as a pale-yellow powder from methyl3-(2-chloro-4-(ethoxycarbonylamino)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(312 mg).

¹H-NMR(CDCl₃): 1.31(3H, t, J=7 Hz), 2.63(3H, s), 4.22(2H, q, J=7 Hz),5.55(2H, s), 6.62(1H, d, J=8 Hz), 7.06(1H, dd, J=8, 2 Hz), 7.72(1H, d,J=2 Hz), 8.16(1H, d, J=8 Hz), 8.22(1H, d, J=8 Hz). MASS(ESI): m/z387(M−1).

PREPARATION EXAMPLE 35-1

To a solution of methyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(300 mg) in dichloromethane (3.0 ml) was added triethylamine (110 mg).To this suspension was added valeryl chloride (115 mg) under ice-coolingand the mixture was stirred for 30 min and at room temperature for 7 hr.Water was added to the reaction mixture and extracted twice withchloroform. The combined organic layer was washed with saturated aqueoussodium hydrogen carbonate solution and saturated brine, dried overanhydrous magnesium sulfate, filtrated, and concentrated under reducedpressure. Hexane was added to the residue. The mixture was crystallized,collected by filtration, and dried under reduced pressure to give methyl3-(2-chloro-4-(N-velerylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylateas thin yellow crystals (328 mg).

¹H-NMR(CDCl₃): 0.88(3H, t, J=7 Hz), 1.28-1.42(2H, m), 1.62-1.73(2H, m),2.34(2H, t, J=7 Hz), 2.52(3H, s), 3.99(3H, s), 5.54(2H, s), 6.33(1H, d,J=8 Hz), 7.07(1H, dd, J=1, 8 Hz), 7.87(1H, d, J=1 Hz), 8.10(1H, d, J=8Hz), 8.16(1H, d, J=8 Hz). MASS(ESI): m/z 415(M+1).

PREPARATION EXAMPLE 35-2

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-(N-valerylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as bright yellow crystals (236 mg) from methyl3-(2-chloro-4-(N-valerylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(300 mg).

¹H-NMR(DMSO-d₆): 0.88(3H, t, J=7 Hz), 1.22-1.37(2H, m), 1.49-1.61(2H,m), 2.28(2H, t, J=7 Hz), 2.51(3H, s), 5.56(2H, s), 6.57(1H, d, J=8 Hz),7.26(1H, dd, J=1, 8 Hz), 8.00(1H, d, J=1 Hz), 8.01(1H, d, J=8 Hz),8.13(1H, d, J=8 Hz). MASS(ESI): m/z 399(M−1).

PREPARATION EXAMPLE 36-1

To a solution of methyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(300 mg) in dichloromethane (3.0 ml) was added pyridine (143 mg). Tothis suspension was added 1-butanesulfonyl chloride (156 mg) underice-cooling and the mixture was stirred for 5 min and at roomtemperature for 7 hr. Water was added to the reaction mixture andextracted twice with chloroform. The combined organic layer was washedwith saturated aqueous sodium hydrogen carbonate solution and saturatedbrine, dried over anhydrous magnesium sulfate, filtrated, andconcentrated under reduced pressure. Methanol was added to the residue.The mixture was crystallized, collected by filtration, and dried underreduced pressure to give methyl3-(4-(N-(1-butanesulfonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylateas ochroid crystals (287 mg).

¹H-NMR(CDCl₃): 0.90(3H, t, J=7 Hz), 1.35-1.49(2H, m), 1.74-1.86(2H, m),2.53(3H, s), 3.10-3.17(2H, m), 3.99(3H, s), 5.61(2H, s), 6.34(1H, d, J=8Hz), 6.90(1H, dd, J=1, 8 Hz), 7.31(1H, d, J=1 Hz), 8.07(1H, d, J=8 Hz),8.13(1H, d, J=8 Hz). MASS(ESI): m/z 451(M+1).

PREPARATION EXAMPLE 36-2

In the same manner as in Preparation Example 14-7,3-(4-(N-(1-butanesulfonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as ochroid crystals (235 mg) from methyl3-(4-(N-(1-butanesulfonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(265 mg).

¹H-NMR(DMSO-d₆): 0.81(3H, t, J=7 Hz), 1.25-1.40(2H, m), 1.54-1.66(2H,m), 3.07-3.15(2H, m), 3.57(3H, s), 5.56(2H, s), 6.60(1H, d, J=8 Hz),7.05(1H, dd, J=1, 8 Hz), 7.34(1H, d, J=1 Hz), 8.00(1H, d, J=8 Hz),8.12(1H, d, J=8 Hz). MASS(ESI): m/z 435(M−1).

PREPARATION EXAMPLE 37-1

In the same manner as in Preparation Example 35-1, methyl3-(2-chloro-4-(N-(t-butylacetyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as thin yellow crystals (346 mg) from methyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(300 mg) and t-butylacetyl chloride (128 mg).

¹H-NMR(CDCl₃): 1.06(9H, s), 2.20(2H, s), 2.49(3H, s), 3.99(3H, s),5.53(2H, s), 6.35(1H, d, J=8 Hz), 7.05(1H, dd, J=1, 8 Hz), 7.95(1H, d,J=1 Hz), 8.05(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz). MASS(ESI): m/z429(M+1).

PREPARATION EXAMPLE 37-2

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-(N-(t-butylacetyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as thin yellow crystals (346 mg) from methyl3-(2-chloro-4-(N-(t-butylacetyl)amino)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(320 mg).

¹H-NMR(DMSO-d₆): 0.99(9H, s), 2.16(2H, s), 3.57(3H, s), 5.56(2H, s),6.55(1H, d, J=8 Hz), 7.25(1H, dd, J=1, 8 Hz), 8.00(1H, d, J=8 Hz),8.01(1H, d, J=1 Hz), 8.11(1H, d, J=8 Hz). MASS(ESI): m/z 415(M+1).

PREPARATION EXAMPLE 38-1

In the same manner as in Preparation Example 4-5,2-(N-acetyl-N-(4-(N,N-bis-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-amino)-6-bromo-3-nitropyridine(2.30 g) was obtained as pale-yellow amorphous from2-acetamido-6-bromo-3-nitropyridine (1.00 g) and4-(N,N-bis(tert-butoxycarbonyl)amino)-2-chlorobenzylbromide (2.10 g).

¹H-NMR(CDCl₃): 1.42(18H, s), 2.19(3H, br. s), 5.38(2H, br. s), 7.06(1H,d, J=8 Hz), 7.21(1H, br. s), 7.49(1H, br. s), 7.62(1H, d, J=8 Hz),8.10(1H, d, J=8 Hz).

PREPARATION EXAMPLE 38-2

In the same manner as in Preparation Example 4-6, a crude product (2.01g) of3-(4-(N,N-bis-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-5-bromo-2-methyl-3H-imidazo[4,5-b]pyridinewas obtained as a pale-yellow oil from2-(N-acetyl-N-(4-(N,N-bis-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)amino)-6-bromo-3-nitropyridine(2.01 g).

PREPARATION EXAMPLE 38-3

A crude product (1.90 g) of3-(4-(N,N-bis-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-5-bromo-2-methyl-3H-imidazo[4,5-b]pyridinewas dissolved in 1,4-dioxane (19 ml) and 1N aqueous sodium hydroxidesolution (7.0 ml) was added, which was followed by refluxing underheating for 8 hr. The mixture was allowed to cool, neutralized andstirred at room temperature for 30 min. The precipitate was collected byfiltration, and washed with water to give3-(4-(N-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-5-bromo-2-methyl-3H-imidazo[4,5-b]pyridine(1.45 g) as a pale-gray powder.

¹H-NMR(CDCl₃): 1.50(9H, s), 2.47(3H, s), 5.50(2H, s), 6.49(1H, br. s),6.55(1H, d, J=8 Hz), 6.93(1H, dd, J=8, 2 Hz), 7.37(1H, d, J=8 Hz),7.72(1H, br. s), 7.83(1H, d, J=8 Hz). MS(ESI): m/z 452(M+1).

PREPARATION EXAMPLE 38-4

In the same manner as in Preparation Example 12-2, methyl3-(4-(N-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(621 mg) was obtained as pale-yellow amorphous from3-(4-(N-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-5-bromo-2-methyl-3H-imidazo[4,5-b]pyridine(500 mg).

¹H-NMR(CDCl₃): 1.50(9H, s), 2.54(3H, s), 4.00(3H, s), 5.61(2H, s),6.56(1H, d, J=8 Hz), 6.60(1H, br. s), 6.91(1H, dd, J=8, 2 Hz), 7.72(1H,br. s), 8.05(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz). MS(ESI): m/z 431(M+1).

PREPARATION EXAMPLE 38-5

In the same manner as in Preparation Example 17-1, methyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatedihydrochloride was obtained as pale-yellow crystals (415 mg) frommethyl3-(4-(N-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(539 mg).

¹H-NMR(DMSO-d₆): 2.62(3H, s), 3.89(3H, s), 5.55(2H, s), 6.65-6.79(2H,m),7.06(1H, s), 8.10(1H, d, J=8 Hz), 8.25(1H, d, J=8 Hz).

PREPARATION EXAMPLE 38-6

In the same manner as in Example 65 to be mentioned later, methyl3-(2-chloro-4-(N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as pale-yellow crystals (310 mg) from methyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatedihydrochloride (390 mg) and isopropyl chlorocarbonate (173 mg).

¹H-NMR(CDCl₃): 1.28(6H, d, J=7 Hz), 2.53(3H, s), 3.99(3H, s),4.95-5.05(1H, m), 5.62(2H, s), 6.58(1H, d, J=8 Hz), 6.98(1H, dd, J=8Hz), 7.70(1H, s), 8.05(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz). MS (ESI):m/z 417(M+1).

PREPARATION EXAMPLE 39

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-(N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as pale-yellow crystals (178 mg) from methyl3-(2-chloro-4-(N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(300 mg).

¹H-NMR(DMSO-d₆): 1.23(6H, d, J=7 Hz), 2.50(3H, overlapped with DMSO-d₆),4.80-4.94(1H, m), 5.55(2H, s), 6.58(1H, d, J=8 Hz), 7.25(1H, dd, J=1, 8Hz), 7.71(1H, s), 8.00(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz).

PREPARATION EXAMPLE 40-1

To a mixture of methyl3-(2-chloro-4-(methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatedihydrochloride (418 mg), pyridine (396 mg) and tetrahydrofuran (4.2 ml)was added dropwise ethyl chlorocarbonate (0.115 ml) under ice-coolingand the mixture was stirred at room temperature for 6 hr. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was washed with saturated brine, dried over magnesium sulfate, andconcentrated to dryness under reduced pressure. The residue waspulverized in diethyl ether to give methyl3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(340 mg) as a white powder.

¹H-NMR(CDCl₃): 1.25(3H, t, J=6 Hz), 2.56(3H, s), 3.26(3H, s),4.00(3H,s), 4.18(2H, q, J=6 Hz), 5.65(2H, s), 6.60(1H, d, J=8 Hz),7.02(1H, dd, J=8, 2 Hz), 7.40(1H, d, J=2 Hz), 8.07(1H, d, J=8 Hz),8.15(1H, d, J=8 Hz). MS(ESI): m/z 417(M+1).

PREPARATION EXAMPLE 40-2

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (287 mg) was obtained as a white powder from methyl3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(335 mg).

¹H-NMR(CDCl₃): 1.26(3H, t, J=6 Hz), 2.65(3H, s), 3.26(3H, s), 4.19(2H,q, J=6 Hz), 5.57(2H, s), 6.60(1H, d, J=8 Hz), 7.08(1H, dd, J=8, 2 Hz),7.45(1H, d, J=2 Hz), 8.18(1H, d, J=8 Hz), 8.24(1H, d, J=8 Hz).

PREPARATION EXAMPLE 41-1

In the same manner as in Example 117 to be mentioned later, methyl3-(2-chloro-4-(3-(n-propyl)ureido)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as a yellow solid (220 mg) from methyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(300 mg) and n-propyl isocyanate (93 mg).

¹H-NMR(CDCl₃): 0.86(3H, t, J=7 Hz), 1.42-1.58(2H, m), 2.49(3H, s),3.15-3.25(2H, m), 3.97(3H, s), 5.49(2H, s), 5.92(1H, d, J=8 Hz),6.84(1H, dd, J=1, 8 Hz), 7.32(1H, d, J=1 Hz), 8.11(1H, d, J=8 Hz),8.17(1H, d, J=8 Hz). MS(ESI): m/z 416(M+1).

PREPARATION EXAMPLE 41-2

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-(3-(n-propyl)ureido)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as yellow crystals (136 mg) from methyl3-(2-chloro-4-(3-(n-propyl)ureido)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(215 mg).

¹H-NMR(DMSO-d₆): 0.85(3H, t, J=7 Hz), 1.35-1.50(2H, m), 2.50(3H,overlapped with DMSO-d₆), 2.96-3.07(2H, m), 5.53(2H, s), 6.50(1H, d, J=8Hz), 7.00(1H, dd, J=1, 8 Hz), 7.85(1H, d, J=1 Hz), 8.00(1H, d, J=8 Hz),8.12(1H, d, J=8 Hz). MS(ESI): m/z 400(M−1).

PREPARATION EXAMPLE 42-1

Methyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(450 mg) was suspended in N,N-dimethylformamide (5 ml) and1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (391 mg),1-hydroxybenzotriazole (276 mg) and 4-bromobutanoic acid (318 mg) wereadded, which was followed by stirring at room temperature for 24 hr.Water (50 ml) was added to the reaction mixture under ice-cooling andthe precipitated crystals were collected by filtration and dried underreduced pressure with heating to give methyl3-(4-((4-bromobutyryl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(436 mg) as pale-yellow crystals.

¹H-NMR(CDCl₃-CD₃OD): 2.10-2.20(2H, m), 2.53(2H, t, J=7 Hz), 3.63(2H, t,J=7 Hz), 4.00(3H, s), 5.62(2H, s), 6.51(1H, d, J=8 Hz), 7.18(1H, dd,J=8, 2 Hz), 7.87(1H, d, J=2 Hz), 8.06(1H, d, J=8 Hz), 8.15(1H, d, J=8Hz)

PREPARATION EXAMPLE 42-2

Methyl3-(4-((4-bromobutyryl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(425 mg) was dissolved in N,N-dimethylformamide (5 ml) and potassiumcarbonate (245 mg) was added, which was followed by stirring at 60° C.for 2 hr. Water was added to the reaction mixture under ice-cooling andthe mixture was extracted with ethyl acetate. The organic layer waswashed successively with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. Ethanol (10 ml) wasadded to the residue, and the mixture was heated and allowed to cool.The precipitated crystals were collected by filtration and dried underreduced pressure with heating to give methyl3-(2-chloro-4-(2-oxotetrahydro-1H-pyrrol-1-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(235 mg) as pale-yellow crystals.

¹H-NMR(CDCl₃): 2.11-2.22(2H, m), 2.54(3H, s), 2.61(2H, t, J=7 Hz),3.80(2H, t, J=7 Hz), 4.00(3H, s), 5.66(2H, s), 6.67(1H, d, J=8 Hz),7.31(1H, dd, J=8, 2 Hz), 7.88(1H, d, J=2 Hz), 8.06(1H, d, J=8 Hz),8.14(1H, d, J=8 Hz)

PREPARATION EXAMPLE 42-3

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-(2-oxotetrahydro-1H-pyrrol-1-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (194 mg) was obtained as pale-yellow crystals from methyl3-(2-chloro-4-(2-oxotetrahydro-1H-pyrrol-1-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(215 mg).

¹H-NMR(DMSO-d₆): 1.98-2.09(2H, m), 2.47-2.52(5H, m), 3.78(2H, t, J=7Hz), 5.60(2H, s), 6.64(1H, d, J=8 Hz), 7.40(1H, dd, J=8, 2 Hz),7.98-8.02(2H, m), 8.13(1H, d, J=8 Hz)

PREPARATION EXAMPLE 43-1

In the same manner as in Example 65, methyl3-(2-chloro-4-((2-chloroethoxycarbonyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(471 mg) was obtained as yellow crystals from methyl3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(450 mg) and 2-chloroethyl chlorocarbonate (253 mg).

¹H-NMR(CDCl₃): 2.59(3H, s), 3.70(2H, t, J=7 Hz), 3.98(3H, s), 4.41(2H,t, J=7 Hz), 5.60(2H, s), 6.48(1H, d, J=8 Hz), 7.01(1H, dd, J=8, 2 Hz),7.64(1H, d, J=2 Hz), 8.11(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz)

PREPARATION EXAMPLE 43-2

Methyl3-(2-chloro-4-((2-chloroethoxycarbonyl)amino)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(240 mg) was dissolved in methanol (3 ml) and a 28% solution (159 mg) ofsodium methylate in methanol was added at room temperature, which wasfollowed by stirring at 60° C. for 2 hr. The reaction mixture wasneutralized with 1N hydrochloric acid under ice-cooling. A saturatedaqueous sodium hydrogen carbonate solution was added and the mixture wasextracted with chloroform. The organic layer was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. Ethyl acetate (5 ml) was added to the residue and themixture was heated and allowed to cool. The precipitated crystals werecollected by filtration and dried under reduced pressure with heating togive methyl3-(2-chloro-4-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(121 mg) as yellow crystals.

¹H-NMR(CDCl₃): 2.54(3H, s), 3.98-4.03(5H, m), 4.49(2H, t, J=7 Hz),5.66(2H, s), 6.71(1H, d, J=8 Hz), 7.21(1H, dd, J=8, 2 Hz), 7.80(1H, d,J=2 Hz), 8.06(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz)

PREPARATION EXAMPLE 43-3

In the same manner as in Preparation Example 14-7, a mixture of3-(2-chloro-4-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid and methyl3-(2-chloro-4-((2-hydroxyethyl)amino)benzyl)-2-methyl-3H-imidazo-[4,5-b]pyridine-5-carboxylatewas obtained as a pale-yellow powder from methyl3-(2-chloro-4-(2-oxo-1,3-oxazolidin-3-yl)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(277 mg).

PREPARATION EXAMPLE 44-1

Fuming nitric acid (26 ml) was cooled to −35° C. and stirred. Methyl4-acetamido-2-chlorobenzoate (6.5 g) was added at from −35° C. to −25°C., and the mixture was stirred for 3 hr. The reaction mixture wasice-cooled and H₂O (260 ml) was poured therein, which was followed bystirring. The resulting crystals were collected by filtration, washedwith water and dried with air. This was applied to flash silica gelcolumn chromatography (silica gel 100 g) to give methyl4-acetamido-2-chloro-5-nitrobenzoate as thin yellow crystals (5.32 g)and methyl 4-acetamido-2-chloro-3-nitrobenzoate as a yellow solid (ca.1.7 g, 22% yield).

methyl 4-acetamido-2-chloro-5-nitrobenzoate

¹H-NMR(CDCl₃): 2.34(3H, s), 3.96(3H, s), 8.83(1H, s), 9.06(1H, s). MS(ESI): m/z 271(M−1).

methyl 4-acetamido-2-chloro-3-nitrobenzoate

¹H-NMR(CDCl₃): 2.23(3H, s), 3.96(3H,s), 7.99(1H, d, J=8 Hz), 8.36(1H, d,J=8 Hz). MS(ESI): m/z 271(M−1).

PREPARATION EXAMPLE 44-2

In the same manner as in Preparation Example 16-5, methyl4-(N-acetyl-N-methylamino)-2-chloro-3-nitrobenzoate was obtained aspale-yellow crystals (1.41 g) from methyl4-(N-acetylamino)-2-chloro-3-nitrobenzoate (1.67 g).

¹H-NMR(CDCl₃): 1.88(3H, s), 3.17(3H, s), 4.00(3H, s), 7.35(1H, d, J=8Hz), 8.05(1H, d, J=8 Hz).

PREPARATION EXAMPLE 44-3

In the same manner as in Preparation Example 4-6, methyl4-chloro-1,2-dimethyl-1H-benzimidazole-5-carboxylate was obtained as acolorless solid (1.09 g) from methyl4-(N-acetyl-N-methylamino)-2-chloro-3-nitrobenzoate (1.39 g).

¹H-NMR(CDCl₃): 2.67(3H, s), 3.76(3H, s), 3.96(3H, s), 7.20(1H, d, J=8Hz), 7.83(1H, d, J=8 Hz). MASS(ESI): m/z 239(M+1).

PREPARATION EXAMPLE 44-4

To a solution of methyl4-chloro-1,2-dimethyl-1H-benzimidazole-5-carboxylate (1.07 g) inanhydrous tetrahydrofuran (11 ml) was added portionwise lithiumborohydride (198 mg) at room temperature and the mixture was stirred for2 hr and heated to 60° C. Thereafter, lithium borohydride (99 mg) wasadded 3 times at 1 hr intervals. The reaction mixture was ice-cooled andadjusted to pH 2 with 1N hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and chloroform was added to the mixture.The precipitated crystals were collected by filtration to give4-chloro-5-hydroxymethyl-1,2-dimethyl-1H-benzimidazole as colorlesscrystals (487 mg). The filtrate was extracted 6 times withchloroform:methanol=5:1. The organic layer was dried over anhydrousmagnesium sulfate, filtrated and concentrated. The residue wascrystallized from isopropyl ether to give the objective product ascolorless crystals (417 mg).

¹H-NMR(DMSO-d₆): 2.54(3H, s), 3.73(3H, s),4.66(2H, d, J=5 Hz), 5.26(1H,d, J=5 Hz), 7.35(1H, d, J=8 Hz), 7.44(1H, d, J=8 Hz). MASS(ESI): m/z211(M+1).

PREPARATION EXAMPLE 44-5

In the same manner as in Preparation Example 19-1,4-chloro-5-chloromethyl-1,2-dimethyl-1H-benzimidazole was obtained as apale-yellow solid (1.20 g) from4-chloro-5-hydroxymethyl-1,2-dimethyl-1H-benzimidazole (885 mg).

¹H-NMR(CDCl₃): 2.75(3H, s), 3.78(3H, s), 4.87(2H, s), 7.24(1H, d, J=8Hz), 7.39(1H, d, J=8 Hz). MASS(ESI): m/z 229(M+1).

PREPARATION EXAMPLE 44-6

In the same manner as in Preparation Example 18-4, methyl3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as a colorless solid (465 mg), and methyl1-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylateas a colorless solid (510 mg), from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (720 mg) and4-chloro-5-chloromethyl-1,2-dimethyl-1H-benzimidazole (949 mg). methyl3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.51(3H, s), 2.66(3H, s), 3.70(3H, s), 4.01(3H, s),5.85(2H, s), 6.70(1H, d, J=8 Hz), 7.04(1H, d, J=8 Hz), 8.05(1H, d, J=8Hz), 8.15(1H, d, J=8 Hz). MASS(ESI): m/z 384(M+1).

methyl1-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.67(3H, s), 2.69(3H, s), 3.72(3H, s), 4.02(3H, s),5.60(2H, s), 6.46(1H, d, J=8 Hz), 7.05(1H, d, J=8 Hz), 7.55(1H, d, J=8Hz), 8.04(1H, d, J=8 Hz). MASS(ESI): m/z 384(M+1).

PREPARATION EXAMPLE 44-7

In the same manner as in Preparation Example 14-7,3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (370 mg) from methyl3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(450 mg).

¹H-NMR(DMSO-d₆): 2.48(3H, s), 2.59(3H, s), 3.72(3H, s), 5.75(2H, s),6.60(1H, d, J=8 Hz), 7.40(1H, d, J=8 Hz), 8.01(1H, d, J=8 Hz), 8.14(1H,d, J=8 Hz). MASS(ESI): m/z 368(M−1).

PREPARATION EXAMPLE 45-1

In the same manner as in Preparation Example 16-5, methyl4-(N-acetyl-N-methylamino)-2-chloro-5-nitrobenzoate was obtained aspale-yellow crystals (1.19 g) from methyl4-acetamido-2-chloro-5-nitrobenzoate (1.5 g).

¹H-NMR(CDCl₃): 1.87(3/2H, s), 2.26(3/2H, s), 3.22(3/2H, s), 3.46(3/2H,s), 3.98(3/2H, s), 4.01(3/2H, s), 7.43(1/2H, s), 7.53(1/2H, s),8.51(1/2H, s), 8.56(1/2H, s). MS(ESI): m/z 287(M+1).

PREPARATION EXAMPLE 45-2

In the same manner as in Preparation Example 4-6, methyl6-chloro-1,2-dimethyl-1H-benzimidazole-5-carboxylate was obtained ascolorless crystals (380 mg) from methyl4-(N-acetyl-N-methylamino)-2-chloro-5-nitrobenzoate (489 mg).

¹H-NMR(CDCl₃): 2.62(3H, s), 3.72(3H, s), 3.95(3H, s), 7.36(1H, s),8.18(1H, s). MASS(ESI): m/z 239(M+1).

PREPARATION EXAMPLE 45-3

In the same manner as in Preparation Example 23-1,6-chloro-5-hydroxymethyl-1,2-dimethyl-1H-benzimidazole was obtained ascolorless crystals (150 mg) from methyl6-chloro-1,2-dimethyl-1H-benzimidazole-5-carboxylate (370 mg).

¹H-NMR(CDCl₃): 2.60(3H, s), 3.70(3H, s), 4.85(2H, s), 7.30(1H, s),7.75(1H, s). MASS(ESI): m/z 211(M+1).

PREPARATION EXAMPLE 45-4

In the same manner as in Preparation Example 19-1,6-chloro-5-chloromethyl-1,2-dimethyl-1H-benzimidazole was obtained as ayellow oil (150 mg) from6-chloro-5-hydroxymethyl-1,2-dimethyl-1H-benzimidazole (140 mg).

¹H-NMR(CDCl₃): 2.66(3H, s), 3.74(3H, s), 4.83(2H, s), 7.38(1H, s),7.79(1H, s). MASS(ESI): m/z 229(M+1).

PREPARATION EXAMPLE 45-5

In the same manner as in Preparation Example 18-4, methyl3-((6-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as pale-yellow crystals (135 mg), and methyl1-((6-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylateas a yellow oil, from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (110 mg) and6-chloro-5-chloromethyl-1,2-dimethyl-1H-benzimidazole (138 mg).

methyl3-((6-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate

¹H-NMR(CDCl₃): 2.51(3H, s), 2.52(3H, s), 3.69(3H, s), 3.97(3H, s),5.76(2H, s), 6.85(1H, s), 7.37(1H, s), 8.07(1H, d, J=8 Hz), 8.13(1H, d,J=8 Hz). MS(ESI): m/z 384(M+1).

PREPARATION EXAMPLE 45-6

In the same manner as in Preparation Example 14-7,3-((6-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl)-2-methyl-3-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as pale-yellow crystals (70 mg) from methyl3-((6-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate(85 mg).

¹H-NMR(DMSO-d₆): 2.56(3H, s), 2.73(3H, s), 3.90(3H, s), 5.76(2H, s),6.95(1H, s), 8.05(1H, d, J=8 Hz), 8.20(1H, d, J=8 Hz), 8.32(1H, s).MS(ESI): m/z 370(M+1).

PREPARATION EXAMPLE 46-1

In the same manner as in Preparation Example 49-1 to be mentioned later,ethyl 3,5-dichloropyridine-2-carboxylate was obtained as a pale-yellowoil (13.4 g) from 2,3,5-trichloropyridine (20 g).

¹H-NMR(CDCl₃): 1.44(1H, t, J=7 Hz), 4.48(2H, d, J=7 Hz), 7.84(1H, d, J=1Hz), 8.54(1H, d, J=1 Hz).

PREPARATION EXAMPLE 46-2

In the same manner as in Preparation Example 31-2,3,5-dichloro-2-(hydroxymethyl)pyridine was obtained as a colorless solid(1.43 g) from ethyl 3,5-dichloropyridine-2-carboxylate (2.0 g).

¹H-NMR(CDCl₃): 3.97(1H, t, J=5 Hz), 4.78(2H, d, J=5 Hz), 7.73(1H, d, J=1Hz), 8.47(1H, d, J=1 Hz).

PREPARATION EXAMPLE 46-3

In the same manner as in Preparation Example 19-1,3,5-dichloro-2-(methanesulfonyloxymethyl)pyridine was obtained as apale-yellow solid (1.01 g) from 3,5-dichloro-2-(hydroxymethyl)-pyridine(700 mg).

¹H-NMR(CDCl₃): 3.13(3H, s), 5.44(2H, s), 7.79(1H, d, J=1 Hz), 8.51(1H,d, J=1 Hz).

PREPARATION EXAMPLE 46-4

In the same manner as in Preparation Example 18-4, methyl3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as pale-yellow crystals (476 mg), and methyl1-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylateas brown amorphous (193 mg), from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (586 mg) and3,5-dichloro-2-(methanesulfonyloxy-methyl)pyridine (1.01 g).

methyl3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.54(3H, s), 3.97(3H, s), 5.74(2H, s), 7.77(1H, br s),8.04(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz), 8.21(1H, d, J=1 Hz).MASS(ESI): m/z 351(M+1).

methyl1-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.71(3H, s), 4.00(3H, s), 5.51(2H, s), 7.64(1H, d, J=8Hz), 7.79(1H, br s), 8.06(1H, d, J=8 Hz), 8.31(1H, br s). MASS(ESI): m/z351(M+1).

PREPARATION EXAMPLE 46-5

In the same manner as in Preparation Example 14-7,3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as pale-brown crystals (346 mg) from methyl3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(460 mg).

¹H-NMR(DMSO-d₆): 2.50(3H, s), 5.78(2H, s), 7.96(1H, d, J=8 Hz), 8.09(1H,d, J=8 Hz), 8.35-8.40(2H, m). MASS(ESI): m/z 335(M−1).

PREPARATION EXAMPLE 47-1

In the same manner as in Preparation Example 18-4, methyl3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (237 mg)was obtained as a white powder from methyl2,7-dimethylimidazo[4,5-b]pyridine-5-carboxylate (150 mg) and3,5-dichloro-2-(methanesulfonyloxymethyl)pyridine(225 mg).

¹H-NMR(CDCl₃): 2.54(3H, s), 2.73(3H, s), 3.96(3H, s), 5.73(2H, s),7.75(1H, d, J=1 Hz), 7.94(1H, s), 8.21(1H, d, J=1 Hz).

PREPARATION EXAMPLE 47-2

In the same manner as in Preparation Example 14-7,3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (207 mg) was obtained as a white powder from methyl3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(234 mg).

¹H-NMR(CDCl₃): 2.68(3H, s), 2.75(3H, s), 5.64(2H, s), 7.80(1H,d, J=1Hz), 8.00(1H, s), 8.26(1H, d, J=1 Hz). MS(ESI): m/z 352(M+1).

PREPARATION EXAMPLE 48-1

Ethyl 6-amino-5-nitronicotinate (9.2 g) was obtained as yellow crystalsfrom 6-amino-5-nitronicotinic acid (18.2 g).

¹H-NMR(CDCl₃): 1.41(3H, t, J=7 Hz), 4.40(2H, q, J=7 Hz), 8.95(1H, d, J=2Hz), 9.01(1H, s). MASS(ESI): m/z 210(M−1)

PREPARATION EXAMPLE 48-2

In the same manner as in Preparation Example 31-2,2-chloro-3-(hydroxymethyl)-6-phenylpyridine was obtained as a colorlesssolid (2.22 g) from methyl 2-chloro-6-phenylnicotinate (2.5 g).

¹H-NMR(CDCl₃): 2.04(1H, t, J=5 Hz), 4.83(2H, d, J=5 Hz), 7.39-7.53 (3H,m), 7.71(1H, d, J=8 Hz), 7.92(1H, d, J=8 Hz), 7.96-8.04(2H, m).

PREPARATION EXAMPLE 48-3

In the same manner as in Preparation Example 19-1,2-chloro-3-(methanesulfonyloxymethyl)-6-phenylpyridine was obtained as acolorless solid (1.10 g) from2-chloro-3-(hydroxymethyl)-6-phenylpyridine (879 mg).

¹H-NMR(CDCl₃): 3.11(3H, s), 5.37(2H, s), 7.41-7.54(3H, m), 7.74(1H, d,J=8 Hz), 7.90(1H, d, J=8 Hz), 7.97-8.05(2H, m).

PREPARATION EXAMPLE 48-4

In the same manner as in Preparation Example 18-4, methyl3-[(2-chloro-6-phenylpyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as colorless crystals (603 mg), and methyl1-[(2-chloro-6-phenylpyridin-2-yl)methyl]-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylateas pale-yellow crystals (400 mg), from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (700 mg) and2-chloro-3-(methanesulfonyloxymethyl)-6-phenylpyridine (1.20 g).

methyl3-[(2-chloro-6-phenylpyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.63(3H, s), 4.00(3H, s), 5.71(2H, s), 7.15(1H, d, J=8Hz), 7.39-7.52(3H, m), 7.54(1H, d, J=8 Hz), 7.91-8.00(2H, m), 8.09(1H,d, J=8 Hz), 8.16(1H, d, J=8 Hz). MASS(ESI): m/z 393(M+1).

methyl1-[(2-chloro-6-phenylpyridin-2-yl)methyl]-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 2.69(3H, s), 4.03(3H, s), 5.48(2H, s), 6.82(1H, d, J=8Hz), 7.41-7.52(3H, m), 7.54(1H, d, J=8 Hz), 7.60(1H, d, J=8 Hz),7.94-8.00(2H, m), 8.11(1H, d, J=8 Hz). MASS(ESI): m/z 393(M+1).

PREPARATION EXAMPLE 48-5

In the same manner as in Preparation Example 14-7,3-[(2-chloro-6-phenylpyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as colorless crystals (523 mg) from methyl3-[(2-chloro-6-phenylpyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(580 mg).

¹H-NMR(DMSO-d₆): 2.59(3H, s), 5.66(2H, s), 7.17(1H, d, J=8 Hz),7.43-7.54(3H, m), 7.87(1H, d, J=8 Hz), 7.97-8.05(2H, m), 8.15(1H, d, J=8Hz). MASS(ESI): m/z 377(M−1).

PREPARATION EXAMPLE 49-1

To a suspension of 5,6-dichloronicotinic acid (5.1 g) in tert-butylalcohol (50 ml) were added triethylamine (2.7 g) and phosphorusdiphenylazide (7.3 g) in a nitrogen atmosphere and the mixture washeated to 80° C. After 8 hr, the reaction mixture was cooled and waterand ethyl acetate were added. The mixture was washed 3 times with water,saturated aqueous sodium hydrogen carbonate solution and saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andthe filtrate was concentrated. The residue was applied to flash silicagel chromatography (silica gel, 30 ml) and eluted with hexane:ethylacetate=5:1-2:1 to give3-(N-(tert-butoxycarbonyl)amino)-5,6-dichloropyridine as a colorlesssolid (6.49 g).

¹H-NMR(CDCl₃): 1.53(9H, s), 6.58(1H, br s), 8.10(1H, d, J=1 Hz),8.25(1H, br s). MASS(ESI): m/z 263(M+1).

PREPARATION EXAMPLE 49-2

To a solution of 3-(N-(tert-butoxycarbonyl)amino)-5,6-dichloropyridine(2.7 g) in anhydrous ethanol (50 ml) were added anhydrous triethylamine(7.38 g), palladium acetate (1.75 g) and1,3-bis(diphenylphosphino)propane (3.21 g). The inside of the reactionvessel was substituted for 1 atm. carbon monoxide and the mixture wasstirred at 60° C. After 10 hr, ethyl acetate (250 ml) was added to thereaction mixture, and an insoluble matter was filtered off. The filtratewas concentrated and the residue was applied to flash silica gel columnchromatography (silica gel, 500 ml) and eluted with hexane:ethylacetate=10:1-5:1-3:1-2:1 to give ethyl5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridine-2-carboxylate as acolorless solid (5.85 g).

¹H-NMR(CDCl₃): 1.43(3H, t, J=7 Hz), 1.53(9H, s), 4.46(2H, q, J=7 Hz),6.75(1H, br s), 8.27-8.35(2H, m). MASS(ESI): m/z 301(M+1).

PREPARATION EXAMPLE 49-3

In the same manner as in Preparation Example 31-2,5-(N-(tert-butoxycarbonyl)amino)-3-chloro-2-hydroxymethylpyridine wasobtained as a colorless gum (4.65 g) from ethyl5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridine-2-carboxylate (5.84g).

¹H-NMR(CDCl₃): 1.53(9H, s), 4.04(1H, t, J=5 Hz), 4.74(2H, d, J=5 Hz),6.59(1H, br s), 8.14(1H, br s), 8.27(1H, d, J=1 Hz). MASS(ESI): m/z259(M+1).

PREPARATION EXAMPLE 49-4

In the same manner as in Preparation Example 19-1,5-(N-(tert-butoxycarbonyl)amino)-3-chloro-2-(methanesulfonyloxy-methyl)pyridinewas obtained as a purple gum (5.7 g) from5-(N-(tert-butoxycarbonyl)amino)-3-chloro-2-hydroxymethylpyridine (4.63g).

¹H-NMR(CDCl₃): 1.53(9H,s), 3.08(3H, s), 5.41(2H, s), 6.77(1H, br s),8.24(1H, br d, J=1 Hz), 8.30(1H, d, J=1 Hz).

PREPARATION EXAMPLE 49-5

In the same manner as in Preparation Example 18-4, methyl3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as a pale-brown solid (1.45 g), and methyl1-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylateas pale-yellow crystals (400 mg), from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (3.2 g) and5-(N-(tert-butoxycarbonyl)-amino)-3-chloro-2-(methanesulfonyloxymethyl)pyridine(5.04 g).

methyl3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 1.51(9H, s), 2.48(3H, s), 3.95(3H, s), 5.66(2H, s),7.52(1H, br s), 7.74(1H, d, J=2 Hz), 8.03(1H, d, J=8 Hz), 8.10(1H, d,J=8 Hz), 8.24(1H, br s). MASS(ESI): m/z 432(M+1).

methyl1-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate:

¹H-NMR(CDCl₃): 1.50(9H, s), 2.72(3H, s), 3.99(3H, s), 5.48(2H, s),7.01(1H, br s), 7.67(1H, d, J=8 Hz), 8.03(1H, d,J=8 Hz), 8.09(1H, d, J=1Hz), 8.29(1H, br s). MASS(ESI): m/z 432(M+1).

PREPARATION EXAMPLE 49-6

In the same manner as in Preparation Example 14-7,3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as a colorless solid (384 mg) from methyl3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(400 mg).

¹H-NMR(DMSO-d₆): 1.46(9H, s), 2.48(3H, s), 3.57(3H, s), 5.70(2H, s),7.96(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz), 8.15(1H, br s), 8.22(1H, d,J=2 Hz), 9.82(1H, br s). MASS(ESI): m/z 416(M−1).

PREPARATION EXAMPLE 50-1

In the same manner as in Preparation Example 17-1, methyl3-(5-amino-3-chloropyridin-2-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatetrihydrochloride was obtained as pale-orange crystals (1.02 g) frommethyl3-((5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(1.04 g).

¹H-NMR(DMSO-d₆): 2.68(3H, s), 3.89(3H, s), 5.67(2H, s), 7.13(1H, d, J=1Hz), 7.65(1H, d, J=1 Hz), 8.13(1H, d, J=8 Hz), 8.29(1H, d, J=8 Hz).MS(ESI): m/z 332(M+1).

PREPARATION EXAMPLE 50-2

In the same manner as in Example 65, methyl3-((5-(N-(ethoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as pale-yellow crystals (326 mg) from methyl3-((5-amino-3-chloropyridin-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatetrihydrochloride (500 mg) and ethyl chlorocarbonate (245 mg).

¹H-NMR(CDCl₃): 1.32(3H, t, J=7 Hz), 2.48(3H, s), 3.94(3H, s), 4.26(2H,q, J=7 Hz), 5.64(2H, s), 7.71(1H, d, J=1 Hz), 8.03(1H, d, J=8 Hz),8.11(1H, d, J=8 Hz), 8.23(1H, s). MS(ESI): m/z 404(M+1).

PREPARATION EXAMPLE 50-3

In the same manner as in Preparation Example 14-7,3-((5-(N-(ethoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as pale-yellow crystals (240 mg) from methyl3-((5-(N-(ethoxycarbonyl)-amino)-3-chloropyridin-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(326 mg).

¹H-NMR(DMSO-d₆): 1.23(3H, t, J=7 Hz), 2.48(3H, s), 4.14(2H, q, J=7 Hz),5.71(2H, s), 7.97(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz), 8.14(1H, s),8.26(1H, s). MS(ESI): m/z 390(M+1).

PREPARATION EXAMPLE 51-1

In the same manner as in Example 65, methyl3-((5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as pale-yellow crystals (406 mg) from methyl3-((5-amino-3-chloropyridin-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatetrihydrochloride (500 mg) and isopropyl chlorocarbonate (277 mg).

¹H-NMR(CDCl₃): 1.30(6H, d, J=7 Hz), 2.49(3H, s), 3.94(3H, s),4.99-5.09(1H, m), 5.66(2H, s), 7.76(1H, d, J=1 Hz), 8.03(1H, d, J=8 Hz),8.11(1H, d, J=8 Hz), 8.23(1H, s). MS(ESI): m/z 418(M+1).

PREPARATION EXAMPLE 51-2

In the same manner as in Preparation Example 14-7,3-((5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as pale-yellow crystals (270 mg) from methyl3-((5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(397 mg).

¹H-NMR(DMSO-d₆): 1.24(6H, d, J=7 Hz), 2.48(3H, s), 4.81-4.95(1H, m),5.71(2H, s), 7.97(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz), 8.14(1H, s),8.26(1H, d, J=1 Hz). MS(ESI): m/z 404(M+1).

PREPARATION EXAMPLE 52-1

In the same manner as in Preparation Example 31-2,2,4-dichloro-5-hydroxymethylpyridine was obtained as colorless crystals(1.5 g) from ethyl 2,4-dichloropyridine-5-carboxylate (3 g).

¹H-NMR(CDCl₃): 4.82(2H, d, J=5 Hz), 7.39(1H, s), 8.48(1H, s).

PREPARATION EXAMPLE 52-2

In the same manner as in Preparation Example 19-1,5-chloromethyl-2,4-dichloropyridine was obtained as a yellow oil (725mg) from 2,4-dichloro-5-hydroxymethylpyridine (660 mg).

¹H-NMR(CDCl₃): 4.66(2H, s), 7.44(1H, s), 8.44(1H, s).

PREPARATION EXAMPLE 52-3

In the same manner as in Preparation Example 18-4, methyl3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylatewas obtained as pale-yellow crystals (640 mg), and methyl1-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylateas a yellow oil, from methyl2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (650 mg) and5-chloromethyl-2,4-dichloropyridine (723 mg).

methyl3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate

¹H-NMR(CDCl₃): 2.62(3H, s), 4.00(3H, s), 5.65(2H, s), 7.45(1H, s), 7.93(1H, s), 8.07(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz). MS(ESI): m/z351(M+1).

PREPARATION EXAMPLE 52-4

In the same manner as in Preparation Example 14-7,3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid was obtained as pale-yellow crystals (385 mg) from methyl3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(500 mg).

¹H-NMR(CDCl₃): 2.68(3H, s), 5.59(2H, s), 7.50(1H, s), 7.84(1H, s),8.20(1H, d, J=8 Hz), 8.25(1H, d, J=8 Hz). MS(ESI): m/z 335(M−1).

PREPARATION EXAMPLE 53-1

In the same manner as in Preparation Example 14-6,2-chloro-4-(1-pentyloxy)toluene (16.3 g) was obtained as a pale-brownoil from 3-chloro-4-methylphenol (10.0 g).

¹H-NMR(CDCl₃): 0.93 (3H, t, J=6 Hz), 1.40(4H, m), 1.76(2H, m), 2.29(3H,s), 3.90(2H, t, J=6 Hz), 6.70(1H, dd, J=8, 2 Hz), 6.90(1H, d, J=2 Hz),7.10(1H, d, J=8 Hz).

PREPARATION EXAMPLE 53-2

In the same manner as in Preparation Example 4-2,2-chloro-4-(1-pentyloxy)benzylbromide (21.9 g) was obtained as apale-yellow solid from 2-chloro-4-(1-pentyloxy)toluene (16.2 g).

¹H-NMR(CDCl₃): 0.93 (3H, t, J=6 Hz), 1.40(4H, m), 1.76(2H, m), 3.93(2H,t, J=6 Hz), 4.58(2H, s), 6.77(1H, dd, J=8, 2 Hz), 6.92(1H, d, J=2 Hz),7.32(1H, d, J=8 Hz).

PREPARATION EXAMPLE 53-3

In the same manner as in Preparation Example 4-5,2-{N-acetyl-N-[2-chloro-4-(1-pentyloxy)benzyl]amino}-6-bromo-3-nitropyridine(8.84 g) was obtained as a pale-yellow solid from2-(acetamido)-6-bromo-3-nitropyridine (5.0 g) and2-chloro-4-(1-pentyloxy)benzylbromide (8.97 g).

¹H-NMR(CDCl₃): 0.93 (3H, t, J=6 Hz), 1.30-1.48(4H, m), 1.77(2H, m),2.23(3H, br.s), 3.91(2H, t, J=6 Hz), 5.29(2H, br.s), 6.74-6.95(2H, m),7.38-7.52(2H, m), 8.08(1H, d, J=8 Hz).

PREPARATION EXAMPLE 53-4

In the same manner as in Preparation Example 4-6,5-bromo-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine(820 mg) was obtained as pale-brown crystals from2-{N-acetyl-N-[2-chloro-4-(1-pentyloxy)benzyl]amino}-6-bromo-3-nitropyridine(1.38 g).

¹H-NMR(CDCl₃): 0.92 (3H, t, J=7 Hz), 1.28-1.49(4H, m), 1.68-1.83 (2H,m), 2.48(3H, s), 3.90(2H, t, J=6 Hz), 5.49(2H, s), 6.58(1H, d, J=9 Hz),6.66(1H, dd, J=9, 2 Hz), 6.96(1H, d, J=2 Hz), 7.37(1H, d, J=8 Hz),7.83(1H, d, J=8 Hz). MASS(ESI): m/z 422, 424(M+1).

PREPARATION EXAMPLE 54-1

In the same manner as in Example 65,3-chloro-N-(ethoxycarbonyl)-4-methylaniline (227 g) was obtained as agray powder from 3-chloro-4-methylaniline (158 g).

¹H-NMR(CDCl₃): 1.32(3H, t, J=6 Hz), 2.32(3H, s), 4.23(2H, q, J=6 Hz),6.50(1H, br.s), 7.13(2H, s), 7.46(1H, s)

PREPARATION EXAMPLE 54-2

In the same manner as in Preparation Example 16-5,3-chloro-N-(ethoxycarbonyl)-N,4-dimethylaniline (1 g) was obtained as acolorless oil from 3-chloro-N-(ethoxycarbonyl)-4-methylaniline (1 g).

¹H-NMR(CDCl₃): 1.24(3H, t, J=7 Hz), 2.35(3H, s), 3.27(3H, s), 4.17(2H,q, J=7 Hz), 7.05(1H, dd, J=1, 8 Hz), 7.19(1H, d, J=8 Hz), 7.25(1H, d,J=1 Hz) MASS(ESI): m/z 228(M+1).

PREPARATION EXAMPLE 54-3

In the same manner as in Preparation Example 4-2, a crude product of4-bromomethyl-3-chloro-N-(ethoxycarbonyl)-N-methylaniline (1.49 g) wasobtained as a brown oil from3-chloro-N-(ethoxycarbonyl)-N,4-dimethylaniline (1.0 g).

¹H-NMR(CDCl₃): 1.29(3H, t, J=6 Hz), 3.29(3H, s), 4.20(2H, q, J=6 Hz),4.58(2H, s), 7.18(1H, dd, J=8, 2 Hz), 7.33(1H, d, J=2 Hz), 7.40(1H, d,J=8 Hz)

PREPARATION EXAMPLE 54-4

In the same manner as in Preparation Example 4-5,6-bromo-2-(N-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-acetamido)-3-nitropyridine(20.8 g) was obtained as a brown oil from2-(acetamido)-6-bromo-3-nitropyridine (13.2 g) and4-bromomethyl-3-chloro-N-(ethoxycarbonyl)-N-methylaniline (26.8 g).

¹H-NMR(CDCl₃): 1.29(3H, t, J=6 Hz), 2.20(3H, br.s), 3.29(3H, s),4.20(2H, q, J=6 Hz), 5.34(2H, br.s), 7.10-7.65(4H, m), 8.10(1H, d, J=8Hz)

PREPARATION EXAMPLE 54-5

In the same manner as in Preparation Example 3-4,5-bromo-3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine(15.5 g) was obtained as a pale-brown powder from6-bromo-2-(N-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)acetamido)-3-nitropyridine(20.8 g).

¹H-NMR(CDCl₃): 1.25(3H, t, J=6 Hz), 2.50(3H, s), 3.29(3H, s), 4.19(2H,q, J=6 Hz), 5.53(2H, s), 6.56(1H, d, J=8 Hz), 7.04(1H, dd, J=8, 1 Hz),7.35-7.45(2H, m), 7.86(1H, d, J=8 Hz)

PREPARATION EXAMPLE 55-1

In the same manner as in Example 65, methyl3-(4-(N-benzyloxycarbonyl-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(159 mg) was obtained as a yellow oil from methyl3-(2-chloro-4-(methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylatedihydrochloride (175 mg) and benzyl chloroformate (107 mg).

¹H-NMR(CDCl₃): 2.55(3H, s), 3.28(3H, s), 4.00(3H, s), 5.16(2H, s),5.65(2H, s), 6.60(1H, d, J=8 Hz), 7.01(1H, dd, J=1, 8 Hz), 7.27-7.44(6H,m), 8.07(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz) MASS(ESI): m/z 479 (M+1).

PREPARATION EXAMPLE 55-2

In the same manner as in Preparation Example 14-7,3-(4-(N-(benzyloxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (132 mg) was obtained as a white powder from methyl3-(4-(N-(benzyloxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate(207 mg).

¹H-NMR(CDCl₃): 2.63(3H, s), 3.30(3H, s), 5.17(2H, s), 5.57(2H, s),6.60(1H, d, J=8 Hz), 7.07(1H, dd, J=8 and 2 Hz), 7.2-7.4(5H, m),7.45(1H, d, J=2 Hz), 8.17(1H, d, J=8 Hz), 8.24(1H, d, J=8 Hz) MASS(ESI):m/e 463 (M−H)⁻.

EXAMPLE 1

To a mixture of3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and N,N-dimethylformamide (2.0 ml) was addedcarbonyldiimidazole (129 mg) and the mixture was stirred at roomtemperature for 2 hr. To the reaction mixture were added(E)-2-(4-pyridyl)ethenesulfonamide (146 mg) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 ml) and the mixture was stirredat room temperature for 2.5 hr. 1N Hydrochloric acid was added to thereaction mixture under ice-cooling to adjust to pH 7, and water (2.0 ml)was added, which was followed by stirring at room temperature for 30min. The precipitate was collected by filtration and washed with waterto give a pale-gray powder (456 mg). This was suspended in ethanol (2.5ml) and the suspension was heated to reflux, and then stirred at roomtemperature for 1 hr. The precipitate was collected by filtration andwashed with ethanol to give3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(E)-[2-(4-pyridyl)ethene]sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine(254 mg) as a white powder.

¹H-NMR(CDCl₃): 2.68(3H, s), 5.63(2H, s), 6.81(1H, d, J=8 Hz),7.30-7.75(11H), 8.13(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz), 8.67(1H, J=6Hz). MASS(ESI): m/z 543(M−1).

EXAMPLE 2

In the same manner as in Example 1,5-[(4-acetoxybutane)-sulfonylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine(118 mg) was obtained from3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (100 mg) and 4-acetoxybutanesulfonamide (62 mg).

¹H-NMR(CDCl₃): 1.78(2H, m), 1.96(2H, m), 2.01(3H, s), 2.69(3H, s),3.59(2H, t, J=6 Hz), 4.05(2H, t, J=6 Hz), 5.62(2H, s), 6.81(1H, d, J=8Hz), 7.34-7.50(4H), 7.55(2H, d, J=8 Hz), 7.71(1H, s), 8.15(1H, d, J=8Hz), 8.21(1H, d, J=8 Hz), 9.88(1H, s). MASS(ESI): m/z 556(M+1).

EXAMPLE 3

In the same manner as in Example 1,3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(4-ethoxycarbonylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (1.01 g) from3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (1.00 g) and (4-ethoxycarbonylbenzene)sulfonamide (910 mg).

¹H-NMR(CDCl₃): 1.39(3H, t, J=7 Hz), 2.68(3H, s), 4.39(2H, q, J=7 Hz),5.62(2H, s), 6.88(1H, d, J=8 Hz), 7.37-7.53(4H, m), 7.59(2H, J=1,8 Hz),7.74(1H, J=1 Hz), 8.05-8.22(6H, m). MS(ESI): m/z 587(M−1).

EXAMPLE 4

In the same manner as in Preparation Example 14-7,3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(4-carboxybenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (809 mg) from3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(4-ethoxycarbonylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine(867 mg).

¹H-NMR(DMSO-d₆): 2.51(3H, overlapped with DMSO-d₆), 5.88(2H, s),6.78(1H, d, J=8 Hz), 7.36-7.51(3H, m), 7.57(1H, J=1,8 Hz), 7.70(2H,J=1,8 Hz), 7.85-7.95(2H, m), 8.10-8.20(5H, m). MS(ESI): m/z 559(M−1).

EXAMPLE 5

In the same manner as in Example 1,3-(2-chloro-4-methoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (178 mg) from3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (180 mg) and 1-pentanesulfonamide (123 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.25-1.50(4H, m), 1.82-1.95(2H, m),2.66(3H, s), 3.51-3.60(2H, m), 3.80(3H, s), 5.51(2H, s), 6.74-6.83(2H,m), 7.01(1H, d, J=1 Hz), 8.11(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz).MASS(ESI): m/z 465(M+1). m.p. 188-189° C.

EXAMPLE 6

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (62 mg) from3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid(80 mg) and 1-butanesulfonamide (50 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.41-1.55(2H, m), 1.80-1.93(2H, m),2.66(3H, s), 3.52-3.60(2H, m), 3.80(3H, s), 5.51(2H, s), 6.74-6.83(2H,m), 7.01(1H, d, J=1 Hz), 8.11(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz).MASS(ESI): m/z 451(M+1). m.p. 175-177° C.

EXAMPLE 7

In the same manner as in Example 1,3-(2-chloro-4-methoxybenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (202 mg) from3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (175 mg) and (4-methylbenzene)sulfonamide (135 mg).

¹H-NMR(CDCl₃): 2.42(3H, s), 2.64(3H, s), 3.82(3H, s), 5.52(2H, s),6.80(2H, s), 7.03(1H, s), 7.34(2H, d, J=8 Hz), 8.01-8.09(4H, m).MASS(ESI): m/z 483 (M−1). m.p. 206-208° C.

EXAMPLE 8

In the same manner as in Example 1,3-(2-chloro-4-ethoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(47mg) was obtained as a white powder from3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (174 mg) and 1-pentanesulfonamide(115 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.23-1.52(4H, m), 1.40(3H, t, J=7Hz), 1.81-1.96(2H, m), 2.65(3H, s), 3.45-3.62(2H, m), 4.01(2H, q, J=7Hz), 5.51(2H, s), 6.68-6.82(2H, m), 6.99(1H, d, J=2 Hz), 8.11(1H, d, J=8Hz), 8.18(1H, d, J=8 Hz), 9.85(1H, br s). MASS(ESI): m/e 477(M−H)⁻. m.p.165-166° C.

EXAMPLE 9

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine(70mg) was obtained as a white powder from3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (174 mg) and 1-butanesulfonamide (104 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.38-1.58(2H, m), 1.40(3H, t, J=7Hz), 1.77-1.94(2H, m), 2.65(3H, s), 3.49-3.62(2H, m), 4.01(2H, q, J=7Hz), 5.51(2H, s), 6.69-6.82(2H, m), 6.99(1H, d, J=2 Hz), 8.11(1H, d, J=8Hz), 8.18(1H, d, J=8 Hz), 9.85(1H, br s). MASS(ESI): m/e 463(M−H)⁻. m.p.151-152° C.

EXAMPLE 10

In the same manner as in Example 1,3-(2-chloro-4-ethoxybenzyl)-2-methyl-5-((1-propylaminosulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (128 mg) from3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (220 mg) and N-(1-propyl)sulfamide (132 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.40(3H, t, J=7 Hz), 1.53-1.67(2H,m), 2.65(3H, s), 3.03(2H, q, J=7 Hz), 4.02(2H, q, J=7 Hz), 5.52(2H, s),6.75(2H, s), 7.00(1H, s), 8.11(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz).MASS(ESI): m/z 464(M−1). m.p. 152-155° C.

EXAMPLE 11

In the same manner as in Example 1,5-((1-butylaminosulfonyl)carbamoyl)-3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (188 mg) from3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and N-(1-butyl)sulfamide (132 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.30-1.45(5H, m), 1.50-1.61(2H, m),2.65(3H, s), 3.06(2H, q, J=7 Hz), 4.01(2H, q, J=7 Hz), 5.52(2H, s),6.75(2H, s), 7.00(1H, s), 8.10(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz).MASS(ESI): m/z 478(M−1). m.p. 175-177° C.

EXAMPLE 12

In the same manner as in Example 1,3-(2-chloro-4-(1-propoxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (169 mg) from3-(2-chloro-4-(1-propoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (185 mg) and 1-pentanesulfonamide (112 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.02(3H, t, J=7 Hz), 1.25-1.50(4H,m), 1.73-1.95(4H, m), 2.65(3H, s), 3.52-3.60(2H, m), 3.90(2H, t, J=7Hz), 5.51(2H, s), 6.76(2H, s), 7.00(1H, s), 8.11(1H, d, J=8 Hz),8.18(1H, d, J=8 Hz). MASS(ESI): m/z 491(M−1). m.p. 131-134° C.

EXAMPLE 13

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-propoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (177 mg) from3-(2-chloro-4-(1-propoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (190 mg) and 1-butanesulfonamide (106 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.02(3H, t, J=7 Hz), 1.41-1.57(2H,m), 1.73-1.93(4H, m), 2.65(3H, s), 3.53-3.60(2H, m), 3.90(2H, t, J=7Hz), 5.51(2H, s), 6.76(2H, s), 7.00(1H, s), 8.11(1H, d, J=8 Hz),8.18(1H, d, J=8 Hz). MASS(ESI): m/z 477(M−1). m.p. 153-154° C.

EXAMPLE 14

In the same manner as in Example 1,3-(2-chloro-4-isopropoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as thin yellow crystals (140 mg) from3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (170 mg) and 1-pentanesulfonamide (107 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.27-1.50(4H, m), 1.32(6H, d, J=7Hz), 1.83-1.95(2H, m), 2.65(3H, s), 3.52-3.60(2H, m), 4.52(1H, sept, J=7Hz), 5.51(2H, s), 6.72(2H, s), 6.99(1H, s), 8.11(1H, d, J=8 Hz),8.19(1H, d, J=8 Hz). MASS(ESI): m/z 491(M−1). m.p. 130-133° C.

EXAMPLE 15

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo-[4,5-b]pyridinewas obtained as thin yellow crystals (119 mg) from3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (180 mg) and 1-butanesulfonamide (103 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.32(6H, d, J=7 Hz), 1.42-1.60(2H,m), 1.80-1.94(2H, m) 2.65(3H, s), 3.52-3.60(2H, m), 4.53(1H, sept, J=7Hz), 5.51(2H, s), 6.72(2H, s), 6.99(1H, d, J=1 Hz), 8.11(1H, d, J=8 Hz),8.19(1H, d, J=8 Hz). MASS(ESI): m/z 477(M−1). m.p. 138-141° C.

EXAMPLE 16

In the same manner as in Example 1,3-(2-chloro-4-isopropoxybenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as thin yellow crystals (161 mg) from3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (155 mg) and (4-methylbenzene)sulfonamide (111 mg).

¹H-NMR(CDCl₃): 1.34(6H, d, J=7 Hz), 2.42(3H, s), 2.64(3H, s), 4.54(1H,sept, J=7 Hz), 5.51(2H, s), 6.75(2H, s), 7.01(1H, s), 7.34(2H, d, J=8Hz), 8.00-8.10(4H, m). MASS(ESI): m/z 511(M−1). m.p. 202-204° C.

EXAMPLE 17

In the same manner as in Example 1,3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (210 mg) from3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (220 mg) and 1-pentanesulfonamide (133 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 0.96(3H, t, J=7 Hz), 1.26-1.57(6H,m), 1.70-1.95(4H, m), 2.65(3H, s), 3.50-3.60(2H, m), 3.94(2H, t, J=7Hz), 5.51(2H, s), 6.75(2H, s), 7.00(1H, s), 8.10(1H, d, J=8 Hz),8.18(1H, d, J=8 Hz). MASS(ESI): m/z 505(M−1). m.p. 133-136° C.

EXAMPLE 18

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (196 mg) from3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (220 mg) and 1-butanesulfonamide (121 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 0.96(3H, t, J=7 Hz), 1.40-1.58(4H,m), 1.70-1.93(4H, m), 2.65(3H, s), 3.52-3.60(2H, m), 3.94(2H, t, J=7Hz), 5.51(2H, s), 6.76(2H, s), 7.00(1H, s), 8.10(1H, d, J=8 Hz),8.18(1H, d, J=8 Hz). MASS(ESI): m/z 491(M−1). m.p. 144-145° C.

EXAMPLE 19

In the same manner as in Example 1,3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (185 mg) from3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and (4-methylbenzene)sulfonamide (137 mg).

¹H-NMR(CDCl₃): 0.97(3H, t, J=7 Hz), 1.41-1.57(2H, m), 1.70-1.84(2H, m),2.42(3H, s), 2.64(3H, s), 3.96(2H, t, J=7 Hz), 5.51(2H, s), 6.78(2H, s),7.02(1H, s), 7.34(2H, d, J=8 Hz), 8.00-8.10(4H, m). MASS(ESI): m/z525(M−1). m.p. 150-153° C.

EXAMPLE 20

In the same manner as in Example 1,3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as thin yellow crystals (211 mg) from3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 1-pentanesulfonamide (117 mg).

¹H-NMR(CDCl₃): 0.85-0.92(6H, m), 1.25-1.50(8H, m), 1.70-1.95(4H, m),2.65(3H, s), 3.51-3.60(2H, m), 3.93(2H, t, J=7 Hz), 5.51(2H, s),6.75(2H, s), 7.00(1H, s), 8.11(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz).MASS(ESI): m/z 521(M+1). m.p. 128-131° C.

EXAMPLE 21

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridinewas obtained as thin yellow crystals (207 mg) from3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (220 mg) and 1-butanesulfonamide (117 mg).

¹H-NMR(CDCl₃): 0.92(3H, t, J=7 Hz), 0.94(3H, t, J=7 Hz), 1.30-1.62(6H,m), 1.70-1.93(4H, m), 2.65(3H, s), 3.51-3.60(2H, m), 3.93(2H, t, J=7Hz), 5.51(2H, s), 6.75(2H, s), 6.99(1H, s), 8.10(1H, d, J=8 Hz),8.18(1H, d, J=8 Hz). MASS(ESI): m/z 507(M+1). m.p. 145-146° C.

EXAMPLE 22

In the same manner as in Example 1,3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-5-((E)-(2-phenylethene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (226 mg) from3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and (E)-(2-phenylethene)sulfonamide (142 mg).

¹H-NMR(CDCl₃): 0.92(3H, t, J=7 Hz), 1.30-1.50(4H, m), 1.71-1.83(2H, m),2.64(3H, s), 3.94(2H, t, J=7 Hz), 5.52(2H, s), 6.68-6.79(2H, m),7.00(1H, d, J=1 Hz), 7.16(1H, d, J=15 Hz), 7.36-7.48(3H, m),7.50-7.59(2H, m), 7.82(1H, d, J=15 Hz), 8.08(1H, d, J=8 Hz), 8.15(1H, d,J=8 Hz). MASS(ESI): m/z 551(M−1). m.p. 180-182° C.

EXAMPLE 23

In the same manner as in Example 1,5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (175 mg) from3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (220 mg) and 5-bromothiophene-2-sulfonamide (206 mg).

¹H-NMR(CDCl₃): 0.93(3H, t, J=7 Hz), 1.30-1.50(4H, m), 1.73-1.85(2H, m),2.66(3H, s), 3.95(2H, t, J=7 Hz), 5.51(2H, s), 6.74-6.83(2H, m),7.01(1H, d, J=1 Hz), 7.09(1H, d, J=5 Hz), 7.73(1H, d, J=5 Hz), 8.07(1H,d, J=8 Hz), 8.11(1H, d, J=8 Hz). MASS(ESI): m/z 611(M−1). m.p. 156-157°C.

EXAMPLE 24

In the same manner as in Example 1,3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-5-[(5-chlorothiophen-2-yl)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (188 mg) from3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (220 mg) and 5-chlorothiophene-2-sulfonamide (168 mg).

¹H-NMR(CDCl₃): 0.93(3H, t, J=7 Hz), 1.30-1.50(4H, m), 1.73-1.85(2H, m),2.66(3H, s), 3.95(2H, t, J=7 Hz), 5.51(2H, s), 6.74-6.84(2H, m),6.95(1H, d, J=5 Hz), 7.00(1H, d, J=1 Hz), 7.77(1H, d, J=5 Hz), 8.07(1H,d, J=8 Hz), 8.11(1H, d, J=8 Hz). MASS(ESI): m/z 565(M−1). m.p. 154-155°C.

EXAMPLE 25

In the same manner as in Example 1,5-((1-propylaminosulfonyl)carbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (193 mg) from3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (220 mg) and N-(1-propyl)sulfamide (118 mg).

¹H-NMR(CDCl₃): 0.92(3H, t, J=7 Hz), 0.94(3H, t, J=7 Hz), 1.30-1.49(4H,m), 1.53-1.84(4H, m), 2.64(3H, s), 3.03(2H, q, J=7 Hz), 3.93(2H, t, J=7Hz), 5.52(2H, s), 6.74(2H, s), 7,00(1H, s), 8.10(1H, d, J=8 Hz),8.16(1H, d, J=8 Hz). MASS(ESI): m/z 506(M−1). m.p. 155-158° C.

EXAMPLE 26

In the same manner as in Example 1,5-((1-butylaminosulfonyl)carbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (202 mg) from3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and N-(1-butyl)sulfamide (118 mg).

¹H-NMR(CDCl₃): 0.84-0.97(6H, m), 1.29-1.61(8H, m), 1.70-1.83(2H, m),2.64(3H, s), 3.05(2H, q, J=7 Hz), 3.93(2H, t, J=7 Hz), 5.51(2H, s),6.74(2H, s), 7,00(1H, s), 8.10(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz).MASS(ESI): m/z 520(M−1). m.p. 136-138° C.

EXAMPLE 27

In the same manner as in Example 1,3-(2-chloro-4-((cyclopentylmethyl)oxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(160mg) was obtained as a white powder from3-(2-chloro-4-((cyclopentylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (164 mg) and 1-pentanesulfonamide (94 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.24-1.97(14H, m), 2.33(1H, sept,J=7 Hz), 2.65(3H, s), 3.49-3.63(2H, m), 3.81(2H, d, J=7 Hz), 5.51(2H,s), 6.75(2H, s), 7.00(1H, s), 8.11(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz),9.86(1H, br s). MASS(ESI): m/e 531(M−H)⁻. m.p. 160-161° C.

EXAMPLE 28

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-((cyclopentylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine(123 mg) was obtained as a white powder from3-(2-chloro-4-((cyclopentylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (126 mg) and 1-butanesulfonamide (68 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.23-1.95(12H, m), 2.33(1H, sept,J=7 Hz), 2.65(3H, s), 3.50-3.63(2H, m), 3.81(2H, d, J=7 Hz), 5.51(2H,s), 6.75(2H, s), 7.00(1H, s), 8.11(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz),9.86(1H, br s). MASS(ESI): m/e 517(M−H)⁻. m.p. 180-181° C.

EXAMPLE 29

In the same manner as in Example 1,3-(2-chloro-4-ethoxybenzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (175 mg) from3-(2-chloro-4-ethoxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (185 mg) and 1-pentanesulfonamide (117 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.25-1.50(10H, m), 1.81-1.95(2H, m),2.91(2H, q, J=7 Hz), 3.50-3.60(2H, m), 4.00(2H, q, J=7 Hz), 5.52(2H, s),6.67-6.75(2H, m), 7.00(1H, d, J=1 Hz), 8.11-8.21(2H, m). MASS(ESI): m/z491(M−1).

EXAMPLE 30

In the same manner as in Example 1,3-(2-chloro-4-ethoxybenzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (196 mg) from3-(2-chloro-4-ethoxybenzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (170 mg) and (4-methylbenzene)sulfonamide (121 mg).

¹H-NMR(CDCl₃): 1.37-1.47(6H, m), 2.42(3H, s), 2.90(2H, q, J=7 Hz),4.03(2H, q, J=7 Hz), 5.52(2H, s), 6.71(1H, d, J=8 Hz), 6.75(1H, dd,J=1,8 Hz), 7.01(1H, d, J=1 Hz), 7.34(2H, d, J=8 Hz), 8.00-8.10(4H, m).MASS(ESI): m/z 511(M−1).

EXAMPLE 31

In the same manner as in Example 1,3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (238 mg) from3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 1-pentanesulfonamide (121 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.02(3H, t, J=7 Hz), 1.20-1.51(7H,m), 1.72-1.95(4H, m), 2.95(2H, q, J=7 Hz), 3.50-3.60(2H, m), 3.90(2H, t,J=7 Hz), 5.52(2H, s), 6.69(1H, d, J=8 Hz), 6.73(1H, dd, J=1,8 Hz),7.00(1H, d, J=1 Hz), 8.11-8.21(2H, m). MASS(ESI): m/z 505(M−1).

EXAMPLE 32

In the same manner as in Example 1,3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (199 mg) from3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (170 mg) and (4-methylbenzene)sulfonamide (117 mg).

¹H-NMR(CDCl₃): 1.03(3H, t, J=7 Hz), 1.43(3H, t, J=7 Hz), 1.80(2H, tq,J=7, 7 Hz), 2.42(3H, s), 2.90(2H, q, J=7 Hz), 3.92(2H, t, J=7 Hz),5.52(2H, s), 6.70(1H, d, J=8 Hz), 6.76(1H, dd, J=1,8 Hz), 7.02(1H, d,J=1 Hz), 7.34(2H, d, J=8 Hz), 8.00-8.10(4H, m). MASS(ESI): m/z 525(M−1).

EXAMPLE 33

In the same manner as in Example 1,3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (187 mg) from3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (180 mg) and 1-pentanesulfonamide (102 mg).

¹H-NMR(CDCl₃): 0.84-0.97(6H, m), 1.27-1.50(11H, m), 1.70-1.95(4H, m),2.92(2H, q, J=7 Hz), 3.50-3.60(2H, m), 3.93(2H, t, J=7 Hz), 5.52(2H, s),6.65-6.75(2H, m), 7.00(1H, d, J=1 Hz), 8.14(1H, d, J=7 Hz), 8.24(1H, d,J=7 Hz). MASS(ESI): m/z 533(M−1).

EXAMPLE 34

In the same manner as in Example 1,3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (180 mg) from3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (160 mg) and (4-methylbenzene)sulfonamide (102 mg).

¹H-NMR(CDCl₃): 0.93(3H, t, J=7 Hz), 1.30-1.50(7H, m), 1.72-1.85(2H, m),2.42(3H, s), 2.90(2H, q, J=7 Hz), 3.95(2H, t, J=7 Hz), 5.52(2H, s),6.70(1H, d, J=8 Hz), 6.75(1H, dd, J=1, 8 Hz), 7.01(1H, d, J=1 Hz),7.33(2H, d, J=8 Hz), 8.00-8.10(4H, m). MASS(ESI): m/z 553(M−1).

EXAMPLE 35

In the same manner as in Example 1,3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (220 mg) from3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (205 mg) and 1-pentanesulfonamide (124 mg).

¹H-NMR(CDCl₃): 0.88(3H, t, J=7 Hz), 1.02(3H, t, J=7 Hz), 1.26-1.50(4H,m), 1.72-1.95(4H, m), 2.64(3H, s), 2.73(3H, s), 3.50-3.60(2H, m),3.89(2H, t, J=7 Hz), 5.49(2H, s), 6.68-6.76(2H, m), 7.00(1H, d, J=1 Hz),7.99(1H, s). MASS(ESI): m/z 505(M−1). m.p. 161-162° C.

EXAMPLE 36

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-[2-chloro-4-(1-propoxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (169 mg) from3-[2-chloro-4-(1-propoxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (180 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.02(3H, t, J=7 Hz), 1.40-1.56(2H,m), 1.72-1.93(4H, m), 2.64(3H, s), 2.73(3H, s), 3.50-3.60(2H, m),3.89(2H, t, J=7 Hz), 5.49(2H, s), 6.72(2H, s), 6.99(1H, br s), 7.99(1H,s), 9.88(1H, br s). MASS(ESI): m/z 491(M−1). m.p. 164-166° C.

EXAMPLE 37

In the same manner as in Example 1,3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (222 mg) from3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and (4-methylbenzene)sulfonamide (137 mg).

¹H-NMR(CDCl₃): 1.03(3H, t, J=7 Hz), 1.75-1.87(2H, m), 2.42(3H, s),2.62(3H, s), 2.66(3H, s), 3.92(2H, t, J=7 Hz), 5.49(2H, s),6.70-6.80(2H, m), 7.01(1H, d, J=1 Hz), 7.33(2H, d, J=8 Hz), 7.88(1H, s),8.04(2H, d, J=8 Hz). MASS(ESI): m/z 525(M−1). m.p. 168-170° C.

EXAMPLE 38

In the same manner as in Example 1,3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (198 mg) from3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg).

¹H-NMR(CDCl₃): 0.83-0.97(6H, m), 1.26-1.49(8H, m), 1.70-1.94(4H, m),2.64(3H, s), 2.73(3H, s), 3.50-3.59(2H, m), 3.91(2H, t, J=7 Hz),5.49(2H, s), 6.71(2H, s), 6.99(1H, br s), 7.99(1H, br s), 9.88(1H, brs). MASS(ESI): m/z 533(M−1). m.p. 149-150° C.

EXAMPLE 39

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine(177 mg) was obtained as colorless crystals from3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg).

¹H-NMR(CDCl₃): 0.86-1.00(6H), 1.30-1.56(6H), 1.70-1.93(4H), 2.64(3H, s),2.74(3H, s), 3.55(2H, t, J=6 Hz), 3.93(2H, t, J=6 Hz), 5.49(2H, s),6.72(2H, s), 6.99(1H, s), 7.99(1H, s), 9.87(1H, br s). MASS(ESI): m/z.m.p. 156-158° C.

EXAMPLE 40

In the same manner as in Example 1,3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (231 mg) from3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.30-1.50(4H, m), 1.71-1.84(2H, m),2.62(3H, s), 2.66(3H, s), 3.95(2H, t, J=7 Hz), 5.49(2H, s),6.69-6.79(2H, m), 6.78(2H, s), 7.01(1H, br s), 7.33(2H, d, J=8 Hz),7.88(1H, s), 8.04(2H, d, J=8 Hz), 10.14(1H, br s). MASS(ESI): m/z553(M−1). m.p. 173-174° C.

EXAMPLE 41

In the same manner as in Example 1,3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(2.16 g) was obtained as a white powder from3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (1.89 g) and 1-pentanesulfonamide (1.00 g).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.23-1.53(4H, m), 1.46(9H, s),1.82-1.97(2H, m), 2.63(3H, s), 3.25(3H, s), 3.50-3.62(2H, m), 5.56(2H,s), 6.64(1H, d, J=8 Hz), 7.10(1H, dd, J=8 and 2 Hz), 7.46(1H, d, J=2Hz), 8.13(1H, d, J=8 Hz), 8.21(1H, d, J=8 Hz), 9.84(1H, br s).MASS(ESI): m/e 562(M−H)⁻. m.p. 160-161° C.

EXAMPLE 42

To a solution of3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(1.91 g) in dichloromethane (19 ml) was added trifluoroacetic acid (14.5ml) under ice-cooling, and the mixture was stirred for 1 hr. The solventwas evaporated and methanol (19 ml) was added to the residue forre-dissolution. Water (9.5 ml) was added and 1N aqueous sodium hydroxidesolution was added dropwise under ice-cooling to adjust to about pH 4.The resulting precipitate was collected by filtration and dried underreduced pressure to give3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(1.53 g) as a white powder.

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.25-1.52(4H, m), 1.79-1.97(2H, m),2.68(3H, s), 2.81(3H, s), 3.48-3.62(2H, m), 3.92(1H, br s), 5.45(2H, s),6.46(1H, dd, J=8 and 2 Hz), 6.63(1H, d, J=2 Hz), 6.80(1H, d, J=8 Hz),8.08(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz), 9.86(1H, br s). MASS(ESI): m/e462(M−H)⁻. m.p. 185-186° C.

EXAMPLE 43

To a suspension of3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(232 mg) in tetrahydrofuran (1.2 ml)-methanol (1.2 ml) were addedacetaldehyde (106 mg), sodium cyanoborohydride (65 mg) and acetic acid(60 mg) at room temperature, and the mixture was stirred. After 2 hr,acetaldehyde (80 mg) was added and the mixture was stirred for 2 hr. Thereaction mixture was diluted with chloroform/methanol (10/1)(10 ml),washed successively with water, 1N hydrochloric acid and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated and the residue was recrystallized from acetone-water to give3-(2-chloro-4-(ethylmethylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(197 mg) as a white powder.

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.11(3H, t, J=7 Hz), 1.24-1.53(4H,m), 1.82-1.97(2H, m), 2.69(3H, s), 2.90(3H, s), 3.37(2H, q, J=7 Hz),3.49-3.63(2H, m), 5.46(2H, s), 6.54(1H, dd, J=8 and 2 Hz), 6.69(1H, d,J=2 Hz), 6.82(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz),9.91(1H, br s). MASS(ESI): m/e 490(M−H)⁻. m.p. 148-149° C.

EXAMPLE 44

In the same manner as in Example 43,3-(2-chloro-4-(methyl-(1-propyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(204mg) was obtained as a white powder from3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(208 mg) and propionaldehyde (267 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 0.91(3H, t, J=7 Hz), 1.26-1.68(6H,m), 1.80-1.97(2H, m), 2.69(3H, s), 2.92(3H, s), 3.17-3.30(2H, m),3.48-3.62(2H, m), 5.46(2H, s), 6.51(1H, dd, J=8 and 2 Hz), 6.67(1H, d,J=2 Hz), 6.80(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz),9.92(1H, br s). MASS(ESI): m/e 504(M−H)⁻. m.p. 129-130° C.

EXAMPLE 45

In the same manner as in Example 43,3-(4-((1-butyl)methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(144 mg) was obtained as a white powder from3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(206 mg) and butylaldehyde (305 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 0.93(3H, t, J=7 Hz), 1.23-1.65(8H,m), 1.82-1.97(2H, m), 2.68(3H, s), 2.91(3H, s), 3.22-3.34(2H, m),3.49-3.62(2H, m), 5.46(2H, s), 6.51(1H, dd, J=9 and 2 Hz), 6.67(1H, d,J=2 Hz), 6.80(1H, d, J=9 Hz), 8.08(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz),9.92(1H, br s). MASS(ESI): m/e 518(M−H)⁻. m.p. 129-130° C.

EXAMPLE 46

In the same manner as in Example 1,3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(2.61 g) was obtained as a colorless powder from3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (1.90 g).

¹H-NMR(CDCl₃): 1.48(9H, s), 2.44(3H, s), 2.62(3H, s), 3.28(3H, s),5,56(2H, s), 6.65(1H, d, J=8 Hz), 7.11(1H, dd, J=8, 2 Hz), 7.34(2H, d,J=8 Hz), 7.47(1H, d, J=2 Hz), 8.03-8.10(4H, m), 10.10(1H, s). MASS(ESI):m/z 582(M−H)⁻.

EXAMPLE 47

In the same manner as in Example 42,3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(1.84g) was obtained as a colorless powder from3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(2.30 g).

¹H-NMR(CDCl₃): 2.42(3H, s), 2.67(3H, s), 2.85(3H, s), 3.96(1H, br),5.45(2H, s), 6.50(1H, dd, J=8, 2 Hz), 6.66(1H, d, J=2 Hz), 6.82(1H, d,J=8 Hz), 7.33(2H, d, J=8 Hz), 7.98-8.05(4H, m), 10.14(1H, s). MASS(ESI):m/z 482(M−H)⁻. m.p. 210-212° C.

EXAMPLE 48

In the same manner as in Example 43,3-(2-chloro-4-(dimethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(55 mg) was obtained as a colorless powder from3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(220 mg) and 37% aqueous formaldehyde solution (184 mg).

¹H-NMR(CDCl₃): 2.42(3H, s), 2.67(3H, s), 2.97(6H, s), 5.47(2H, s),6.60(1H, dd, J=8, 2 Hz), 6.74(1H, d, J=2 Hz), 6.86(1H, d, J=8 Hz),7.33(2H, d, J=8 Hz), 7.98-8.05(4H, m), 10.17(1H, s). MASS(ESI): m/e596(M−H)⁻. m.p. 218-220° C.

EXAMPLE 49

In the same manner as in Example 43,3-(2-chloro-4-(ethylmethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(176 mg) was obtained as pale-yellow crystals from3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(220 mg) and acetaldehyde (200 mg).

¹H-NMR(CDCl₃): 1.13(3H, t, J=7 Hz), 2.42(3H, s), 2.67(3H, s), 2.92(3H,s), 3.39(2H, q, J=7 Hz), 5.46(2H, s), 6.57(1H, dd, J=8, 2 Hz), 6.71(1H,d, J=2 Hz), 6.83(1H, d, J=8 Hz), 7.33(2H, d, J=8 Hz), 7.98-8.06(4H, m),10.19(1H, s). MASS(ESI): m/z 511(M−H)⁻. m.p. 205-207° C.

EXAMPLE 50

In the same manner as in Example 43,3-(2-chloro-4-(methyl-(1-propyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(198 mg) was obtained as pale-yellow crystals from3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(220 mg) and propionealdehyde (343 mg).

¹H-NMR(CDCl₃): 0.92(3H, t, J=7 Hz), 1.54-1.67(2H, m), 2.42(3H, s),2.67(3H, s), 2.94(3H, s), 3.27(2H, t, J=7 Hz), 5.46(2H, s), 6.55(1H, dd,J=8, 2 Hz), 6.69(1H, d, J=2 Hz), 6.82(1H, d, J=8 Hz), 7.33(2H, d, J=8Hz), 7.98-8.06(4H, m), 10.19(1H, s). MASS(ESI): m/z 524(M−H)⁻. m.p.178-180° C.

EXAMPLE 51

In the same manner as in Example 43,3-(2-chloro-4-((1-butyl)methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(207 mg) was obtained as pale-yellow crystals from3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(220 mg) and butylaldehyde (426 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.27-1.40(2H, m), 1.50-1.60(2H, m),2.42(3H, s), 2.67(3H, s), 2.94(3H, s), 3.30(2H, t, J=7 Hz), 5.46(2H, s),6.54(1H, dd, J=8, 2 Hz), 6.69(1H, d, J=2 Hz), 6.81(1H, d, J=8 Hz),7.33(2H, d, J=8 Hz), 7.98-8.05(4H, m), 10.19(1H, s). MASS(ESI): m/z538(M−H)⁻. m.p. 129-132° C.

EXAMPLE 52

In the same manner as in Example 1,3-(2-chloro-4-(methyl-(1-pentyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(137mg) was obtained as pale-yellow crystals from3-(2-chloro-4-(methyl-(1-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (180 mg) and 1-pentanesulfonamide (306 mg).

¹H-NMR(CDCl₃): 0.88(6H, t, J=7 Hz), 1.22-1.47(8H, m), 1.47-1.60(2H, m),1.85-1.95(2H, m), 2.68(3H, s), 2.92(3H, s), 3.26(2H, t, J=7 Hz),3.55(2H, t, J=7 Hz), 5.46(2H, s), 6.50(1H, dd, J=8, 2 Hz), 6.67(1H, d,J=2 Hz), 6.78(1H, d, J=8 Hz), 8.06(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz),9.92(1H, s). MASS(ESI): m/z 532(M−H)⁻. m.p. 83-85° C.

EXAMPLE 53

In the same manner as in Example 1,3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(105 mg) was obtained as a white powder from3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (106 mg) and 1-pentanesulfonamide (60 mg).

¹H-NMR(CDCl₃): 0.80-2.00(17H, m), 0.89(3H, t, J=7 Hz), 2.69(3H, s),2.93(3H, s), 3.09(2H, d, J=7 Hz), 3.49-3.64(2H, m), 5.47(2H, s),6.48(1H, dd, J=9 and 2 Hz), 6.65(1H, d, J=2 Hz), 6.78(1H, d, J=9 Hz),8.08(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz), 9.92(1H, br s). MASS(ESI): m/e558(M−H)⁻. m.p. 169-170° C.

EXAMPLE 54

In the same manner as in Example 1,3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(101mg) was obtained as a white powder from3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (99 mg) and (4-methylbenzene)sulfonamide (62 mg).

¹H-NMR(CDCl₃): 0.83-1.34(6H, m), 1.60-1.82(5H, m), 2.42(3H, s), 2.67(3H,s), 2.96(3H, s), 3.12(2H, d, J=7 Hz), 5.47(2H, s), 6.52(1H, dd, J=9 and2 Hz), 6.67(1H, d, J=2 Hz), 6.80(1H, d, J=9 Hz), 7.33(2H, d, J=8 Hz),7.97-8.10(4H, m), 10.20(1H, br s). MASS(ESI): m/e 578(M−H)⁻. m.p.194-195° C.

EXAMPLE 55

In the same manner as in Example 1,3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (161 mg) from3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (160 mg) and (4-methylbenzene)sulfonamide (104 mg).

¹H-NMR(CDCl₃): 2.41(3H, s), 2.59(3H, s), 2.68(3H, s), 5.50(2H, s),6.59(1H, d, J=8 Hz), 7.30-7.38(3H, m), 7.68(1H, d, J=2 Hz), 7.90(1H, brs), 8.04(2H, d, J=8 Hz). MASS(ESI): m/z 547(M−1). m.p. 206-208° C.

EXAMPLE 56

3-(4-Bromo-2-chlorobenzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine(400 mg) was dissolved in toluene (5 ml), and sodium tert-butylate (98mg), N-methylethylamine (216 mg),(R)-(+)-2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl (3.4 mg) andtris(dibenzylidene-acetone) dipalladium(0)(1.7 mg) were successivelyadded in a nitrogen atmosphere. The mixture was stirred at 100° C. for24 hr. The reaction mixture was concentrated under reduced pressure, andwater was added. 1N Hydrochloric acid was added to adjust to pH 7 andthe mixture was extracted with chlorform:methanol=4:1. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. To the residue was addedethanol (5.0 ml), and the mixture was heated and allowed to cool. Theprecipitated crystals were collected by filtration. The crystals weredissolved in N,N-dimethylformamide (1.8 ml) and water (1.2 ml) wasgradually added on an oil bath at 80° C. The mixture was allowed to cooland precipitated crystals were collected by filtration and dried underreduced pressure with heating to give3-(2-chloro-4-(ethylmethylamino)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine(79 mg) as pale-yellow crystals.

¹H-NMR(CDCl₃): 1.14(3H, t, J=7 Hz), 2.42(3H, s), 2.65(3H, s), 2.66(3H,s), 2.92(3H, s), 3.39(2H, q, J=7 Hz), 5.44(2H, s), 6.55(1H, dd, J=8, 2Hz), 6.72(1H, d, J=2 Hz), 6.78(1H, d, J=8 Hz), 7.32(2H, d, J=8 Hz),7.85(1H, s), 8.04(2H, d, J=8 Hz), 10.20(1H, s). MASS(ESI): m/z524(M−H)⁻. m.p. 212-215° C.

EXAMPLE 57

In the same manner as in Example 1,3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as a colorless solid (108 mg) from3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (130 mg) and 1-pentanesulfonamide (80 mg).

¹H-NMR(CDCl₃): 0.88(3H, t, J=7 Hz), 1.26-1.49(4H, m), 1.82-1.95(2H, m),2.69(3H, s), 3.51-3.60(2H, m), 5.76(2H, s), 8.05(1H, br s), 8.12(1H, d,J=8 Hz), 8.19(1H, d, J=8 Hz), 8.58(1H, br s), 9.88(1H, br s). MASS(ESI):m/z 502(M−1). m.p. 169-170° C.

EXAMPLE 58

In the same manner as in Example 1,3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as a colorless solid (271 mg) from3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (130 mg) and (4-methylbenzene)sulfonamide (90 mg).

¹H-NMR(CDCl₃): 2.42(3H, s), 2.67(3H, s), 5.77(2H, s), 7.33(2H, d, J=8Hz), 8.01-8.11(4H, m), 8.59(1H, br s), 10.16(1H, br s). MASS(ESI): m/z524(M+1). m.p. 231-232° C.

EXAMPLE 59

In the same manner as in Example 1,3-(2-chloro-4-phenylbenzyl)-2-ethoxy-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas synthesized as a pale-brown powder (26 mg).

¹H-NMR(CDCl₃): 0.85(3H, t, J=6 Hz), 1.20-1.45(4H), 1.54(3H, t, J=7 Hz),1.85(2H, m), 3.52(2H, t, J=6 Hz), 4.74(2H, q, J=7 Hz), 5.45(2H, s),7.20(1H, d, J=8 Hz), 7.34-7.50(4H), 7.56(2H, d, J=8 Hz), 7.68(1H, d, J=1Hz), 7.88(1H, d, J=8 Hz), 8.10(1H, d, J=8 Hz). MASS(ESI): m/z 539(M).

EXAMPLE 60

In the same manner as in Example 1,3-(2-chloro-4phenylbenzyl)-2-methyl-5-[(1-propylaminosulfonyl)carbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (209 mg) from3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and N-(1-propyl)sulfonamide (110 mg).

¹H-NMR(CDCl₃): 0.90(3H, t, J=7 Hz), 1.48-1.64(2H, m), 2.68(3H, s),2.94-3.05(2H, m), 5.30(1H, br s), 5.63(2H, s), 6.80(1H, d, J=8 Hz),7.34-7.50(4H, m), 7.55(2H, br d, J=8 Hz), 7.71(1H, br s), 8.12(1H, d,J=8 Hz), 8.19(1H, d, J=8 Hz), 9.95(1H, br s). MASS(ESI): m/z 496(M−1).m.p. 208-209° C.

EXAMPLE 61

In the same manner as in Example 1,3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as a colorless solid (173 mg) from3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (180 mg) and p-toluenesulfonamide (120 mg).

¹H-NMR(CDCl₃): 2.42(3H, s), 2.66(3H, s), 2.67(3H, s), 5.74(2H, s),7.32(2H, br d, J=8 Hz), 7.88(1H, s), 8.00-8.08(3H, m), 8.58(1H, br s),10.16(1H, br s). MASS(ESI): m/z 536(M−1). m.p. 211-212° C.

EXAMPLE 62

In the same manner as in Example 1,3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as a colorless solid (167 mg) from3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (180 mg) and 1-pentanesulfonamide (121 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.26-1.50(4H, m), 1.82-1.95(2H, m),2.64(3H, s), 3.51-3.61(2H, m), 5.56(2H, s), 7.03(1H, d, J=8 Hz),7.25(1H, d, J=8 Hz), 8.17(1H, d, J=8 Hz), 8.24(1H, d, J=8 Hz), 9.73(1H,br s). m.p. 233-234° C.

EXAMPLE 63

In the same manner as in Example 1,3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as a colorless solid (165 mg) from3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (180 mg) and p-toluenesulfonamide (137 mg).

¹H-NMR(CDCl₃): 2.43(3H, s), 2.63(3H, s), 5.57(2H, s), 7.05(1H, d, J=8Hz), 7.25(1H, d, J=8 Hz), 7.35(2H, br d, J=8 Hz), 8.05(2H, br d, J=8Hz), 8.09(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz), 10.05(1H, br s). m.p.226-227° C.

EXAMPLE 64

To a suspension of3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(188 mg) in dichloromethane (1.9 ml) were added pyridine (58 mg) andpivaloyl chloride (65 mg) at room temperature and the mixture wasstirred for 2 days. The reaction mixture was diluted with chloroform,washed successively with water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated and ethanol wasadded to the residue to give crude crystals. Ethanol was evaporated, andthe residue was recrystallized from acetone-water to give3-(2-chloro-4-(methyl(pivaloyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(199 mg) as a white powder.

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.09(9H, s), 1.25-1.52(4H, m),1.82-1.97(2H, m), 2.63(3H, s), 3.23(3H, s), 3.52-3.62(2H, m), 5.61(2H,s), 6.68(1H, d, J=9 Hz), 7.07(1H, dd, J=9 and 2 Hz), 7.39(1H, d, J=2Hz), 8.16(1H, d, J=8 Hz), 8.23(1H, d, J=8 Hz), 9.82(1H, br s).MASS(ESI): m/e 546(M−H)⁻. m.p. 207-208° C.

EXAMPLE 65

To a suspension of3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(278 mg) in dichloromethane (3 ml) were added pyridine (148 mg) andethyl chlorocarbonate (129 mg) under ice-cooling, and the mixture wasstirred for 24 hr. The solvent was evaporated and the residue waspurified by silica gel column chromatography (ethyl acetate) andrecrystallized from ethyl acetate-hexane to give3-(4-(N-(ethoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(126 mg) as a white powder.

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.25-1.52(4H, m), 1.27(3H, t, J=7Hz), 1.83-1.98(2H, m), 2.65(3H, s), 3.30(3H, s), 3.50-3.62(2H, m),4.19(2H, q, J=7 Hz), 5.56(2H, s), 6.65(1H, d, J=8 Hz), 7.11(1H, dd, J=8and 2 Hz), 7.46(1H, d, J=2 Hz), 8.14(1H, d, J=8 Hz), 8.21(1H, d, J=8Hz), 9.82(1H, br s). MASS(ESI): m/e 534(M−H)⁻. m.p. 149-150° C.

EXAMPLE 66

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (147 mg) from3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 1-butanesulfonamide (102 mg).

¹H-NMR(CDCl₃): 0.87-0.99(6H, m), 1.30-1.58(9H, m), 1.70-1.93(4H, m),2.91(2H, q, J=7 Hz), 3.50-3.60(2H, m), 3.93(2H, t, J=7 Hz), 5.51(2H, s),6.65-6.75(2H, m), 7.00(1H, s), 8.11-8.22(2H, m). MS(ESI): m/z 519(M−1).m.p. 140-142° C.

EXAMPLE 67

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (184 mg) from3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 1-butanesulfonamide (96.2 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 0.99-1.56(11H, m), 1.65-1.94(7H, m),2.92(2H, q, J=7 Hz), 3.52-3.60(2H, m), 3.72(2H, d, J=7 Hz), 5.52(2H, s),6.65-75(2H, m), 7.00(1H, d, J=1 Hz), 8.15(1H, d, J=8 Hz), 8.19(1H, d,J=8 Hz). MS(ESI): m/z 545(M−1). m.p. 145-146° C.

EXAMPLE 68

In the same manner as in Example 1,3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (183 mg) from3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 1-pentanesulfonamide (106 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 0.95-1.50(13H, m), 1.63-1.95(7H, m),2.92(2H, q, J=7 Hz), 3.52-3.60(2H, m), 3.72(2H, d, J=7 Hz), 5.52(2H, s),6.65-75(2H, m), 7.00(1H, d, J=1 Hz), 8.15(1H, d, J=8 Hz), 8.19(1H, d,J=8 Hz). MS(ESI): m/z 559(M−1). m.p. 137-139° C.

EXAMPLE 69

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (206 mg) from3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 1-butanesulfonamide (112 mg).

¹H-NMR(CDCl₃): 0.90(3H, t, J=8 Hz), 1.36-1.52(2H, m), 1.76-1.89(2H, m),2.66(3H, s), 3.49-3.59(2H, m), 5.58(2H, s), 6.49(1H, m), 6.70(1H, d, J=5Hz), 6.81(1H, d, J=8 Hz), 7.46-7.51(2H, m), 7.78(1H, d, J=1 Hz),8.13(1H, d, J=8 Hz), 8.20(1H, d, J=8 Hz), 9.83(1H, br s). MASS(ESI): m/z485(M−1). m.p. 208-209° C.

EXAMPLE 70

In the same manner as in Example 1,3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (199 mg) from3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 1-pentanesulfonamide (120 mg).

¹H-NMR(CDCl₃): 0.86(3H, t, J=8 Hz), 1.22-1.45(4H, m), 1.78-1.90(2H, m),2.66(3H, s), 3.49-3.56(2H, m), 5.59(2H, s), 6.49(1H, m), 6.70(1H, d, J=5Hz), 6.80(1H, d, J=8 Hz), 7.45-7.51(2H, m), 7.77(1H, d, J=1 Hz),8.13(1H, d, J=8 Hz), 8.20(1H, d, J=8 Hz), 9.83(1H, br s). MASS(ESI): m/z499(M−1). m.p. 184-185° C.

EXAMPLE 71

In the same manner as in Example 1,3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (205 mg) from3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and p-toluenesulfonamide (140 mg).

¹H-NMR(CDCl₃): 2.39(3H, s), 2.65(3H, s), 5.58(2H, s), 6.51(1H, m),6.73(1H, d, J=5 Hz), 6.85(1H, d, J=8 Hz), 7.27(2H, d, J=8 Hz),7.50-7.56(2H, m), 7.79(1H, d, J=1 Hz), 7.99(2H, d, J=8 Hz), 8.05(1H, d,J=8 Hz), 8.08(1H, d, J=8 Hz), 10.09(1H, br s). MASS(ESI): m/z 519(M−1).m.p. 207-208° C.

EXAMPLE 72

In the same manner as in Example 1,3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as a colorless solid (167 mg) from3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (170 mg) and 1-pentanesulfonamide (100 mg).

¹H-NMR(CDCl₃): 0.90(3H, t, J=7 Hz), 1.16(3H, t, J=7 Hz), 1.27-1.53(13H,m), 1.84-1.96(2H, m), 2.62(3H, s), 3.66(3H, q, J=7 Hz), 5.57(2H, s),6.63(1H, d, J=8 Hz), 7.05(1H, dd, J=8 Hz), 7.41(1H, d, J=1 Hz), 8.14(1H,d, J=8 Hz), 8.21(1H, d, J=8 Hz), 9.85(1H, br s). MASS(ESI): m/z576(M−1). m.p. 131-132° C.

EXAMPLE 73

In the same manner as in Example 1,3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(631mg) was obtained as a pale-yellow powder from3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (519 mg) and (4-methylbenzene)sulfonamide (300 mg).

¹H-NMR(CDCl₃): 1.17(3H, t, J=7 Hz), 1.46(9H, s), 2.42(3H, s), 2.61(3H,s), 3.68(2H, q, J=7 Hz), 5.57(2H, s), 6.63(1H, d, J=8 Hz), 7.05(1H, dd,J=8, 2 Hz), 7.34(2H, d, J=8 Hz), 7.43(1H, d, J=2 Hz), 8.04-8.12(4H, m),10.13(1H, s). MASS(ESI): m/z 596(M−H)⁻. m.p. 205-207° C.

EXAMPLE 74

In the same manner as in Example 42,3-(2-chloro-4-(ethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(349 mg) was obtained as colorless crystals from3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(587 mg).

¹H-NMR(CDCl₃): 1.26(3H, t, J=7 Hz), 2.42(3H, s), 2.66(3H, s), 3.17(2H,q, J=7 Hz), 3.80(1H, br s), 5.45(2H, s), 6.49(1H, dd, J=8, 2 Hz),6.65(1H, d, J=2 Hz), 6.80(1H, d, J=8 Hz), 7.33(2H, d, J=8 Hz),7.98-8.17(4H, m), 10.13(1H, s). MASS(ESI): m/z 496(M−H)⁻. m.p. 235-237°C.

EXAMPLE 75

In the same manner as in Example 43,3-(2-chloro-4-(N,N-diethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(125 mg) was obtained as colorless crystals from3-(2-chloro-4-(ethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(155 mg) and acetaldehyde (137 mg).

¹H-NMR(CDCl₃): 1.66(6H, t, J=7 Hz), 2.42(3H, s), 2.68(3H, s), 3.34(4H,q, J=7 Hz), 5.46(2H, s), 6.52(1H, dd, J=8, 2 Hz), 6.69(1H, d, J=2 Hz),6.80(1H, d, J=8 Hz), 7.33(2H, d, J=8 Hz), 7.99-8.07(4H, m), 10.20(1H,s). MASS(ESI): m/z 524(M−H)⁻. m.p. 185-187° C.

EXAMPLE 76

In the same manner as in Example 43,3-(2-chloro-4-(N-ethyl-N-(1-pentyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(80 mg) was obtained as colorless crystals from3-(2-chloro-4-(ethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(210 mg) and valeraldehyde (726 mg).

¹H-NMR(CDCl₃): 0.91(3H, t, J=7 Hz), 0.15(3H, t, J=7 Hz), 1.24-1.40(4H,m), 1.54-1.64(2H, m), 2.42(3H, s), 2.67(3H, s), 3.22(2H, t, J=7 Hz),3.34(2H, q, J=7 Hz), 5.46(2H, s), 6.49(1H, dd, J=8, 2 Hz), 6.66(1H, d,J=2 Hz), 6.77(1H, d, J=8 Hz), 7.33(2H, d, J=8 Hz), 7.98-8.07(4H, m),10.21(1H, s). MASS(ESI): m/z 566(M−H)⁻. m.p. 162-164° C.

EXAMPLE 77

In the same manner as in Example 1,3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(185 mg) was obtained as pale-yellow crystals from3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 1-pentanesulfonamide (102 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.25-1.50(4H, m), 1.46(9H, s),1.83-1.95(2H, m), 2.62(3H, s), 2.74(3H, s), 3.25(3H, s), 3.56(2H, t, J=7Hz), 5.53(2H, s), 6.60(1H, d, J=8 Hz), 7.08(1H, dd, J=8, 2 Hz), 7.44(1H,d, J=2 Hz), 8.02(1H, s), 9.87(1H, s). MASS(ESI): m/z 576(M−H)⁻. m.p.193-194° C.

EXAMPLE 78

In the same manner as in Example 1,3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(625mg) was obtained as pale-yellow crystals from3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (587 mg) and (4-methylbenzene)sulfonamide (339 mg).

¹H-NMR(CDCl₃): 1.47(9H, s), 2.42(3H, s), 2.60(3H, s), 2.68(3H, s),3.26(3H, s), 5.54(2H, s), 6.60(1H, d, J=8 Hz), 7.08(1H, dd, J=8, 2 Hz),7.33(2H, d, J=8 Hz), 7.47(1H, d, J=2 Hz), 7.91(1H, s), 8.05(2H, d, J=8Hz), 10.13(1H, s). MASS(ESI): m/z 596(M−H)⁻. m.p. 194-196° C.

EXAMPLE 79

In the same manner as in Example 42,3-(2-chloro-4-(methylamino)benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(300 mg) was obtained as pale-yellow crystals from3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(420 mg).

¹H-NMR(CDCl₃): 2.42(3H, s), 2.65(3H, s), 2.65(3H, s), 2.84(3H, s),3.95(1H, br s), 5.43(2H, s), 6.48(1H, dd, J=8, 2 Hz), 6.65(1H, d, J=2Hz), 6.76(1H, d, J=8 Hz), 7.32(2H, d, J=8 Hz), 7.85(1H, s), 8.04(2H, d,J=8 Hz), 10.15(1H, s). MASS(ESI): m/z 496(M−H)⁻.

EXAMPLE 80

In the same manner as in Example 43,3-(2-chloro-4-(N-methyl-N-propylamino)benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(274 mg) was obtained as pale-yellow crystals from3-(2-chloro-4-(methylamino)benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(286 mg) and propionealdehyde (1.00 g).

¹H-NMR(CDCl₃): 0.92(3H, t, J=7 Hz), 1.54-1.66(2H, m), 2.42(3H, s),2.65(3H, s), 2.66(3H, s), 2.94(3H, s), 3.26(2H, t, J=7 Hz), 5.44(2H, s),6.53(1H, dd, J=8, 2 Hz), 6.69(1H, d, J=2 Hz), 6.77(1H, d, J=8 Hz),7.32(2H, d, J=8 Hz), 7.85(1H, s), 8.04(2H, d, J=8 Hz) MASS(ESI): m/z538(M−H)⁻. m.p. 194-195° C.

EXAMPLE 81

In the same manner as in Example 1,3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(185 mg) was obtained as pale-brown crystals from3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (220 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=6 Hz), 1.15(3H, t, J=6 Hz), 1.35(4H, m),1.45(9H, s), 1.89(2H, m), 2.62(3H, s), 2.75(3H, s), 3.55(2H, m),3.66(2H, q, J=6 Hz), 5.55(2H, s), 6.59(1H, d, J=8 Hz), 7.03(1H, dd, J=8,2 Hz), 7.39(1H, d, J=2 Hz), 8.03(1H, s), 9.85(1H, br. s). MASS(ESI): m/z592(M). m.p. 190-191° C.

EXAMPLE 82

In the same manner as in Example 1,3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(170 mg) was obtained as pale-brown crystals from3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (220 mg).

¹H-NMR(CDCl₃): 1.17(3H, t, J=6 Hz), 1.45(9H, s), 2.42(3H, s), 2.60(3H,s), 2.69(3H, s), 3.68(2H, q, J=6 Hz), 5.55(2H, s), 6.59(1H, d, J=8 Hz),7.03(1H, dd, J=8, 2 Hz), 7.33(2H, d, J=8 Hz), 7.41(1H, d, J=2 Hz),7.92(1H, s), 8.05(2H, d, J=8 Hz), 10.12(1H, br. s). MASS(ESI): m/z612(M). m.p. 163-165° C.

EXAMPLE 83

In the same manner as in Example 1,3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(198 mg) was obtained as colorless crystals from3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 1-pentanesulfonamide (124 mg).

¹H-NMR(CDCl₃): 0.87(3H, t, J=7 Hz), 1.25-1.45(4H, m), 1.80-1.90(2H, m),2.68(3H, s), 3.54(2H, t, J=7 Hz), 5.58(2H, s), 6.35(2H, t, J=2 Hz),6.86(1H, d, J=8 Hz), 7.07(2H, t, J=2 Hz), 7.25(1H, dd, J=8, 2 Hz),7.52(1H, d, J=2 Hz), 8.14(1H, d, J=8 Hz), 8.20(1H, d, J=8 Hz), 9.81(1H,s). MASS(ESI): m/z 498(M−H)⁻. m.p. 171-172° C.

EXAMPLE 84

In the same manner as in Example 1,3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(222 mg) was obtained as colorless crystals from3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 4-methylbenzenesulfonamide (140 mg).

¹H-NMR(CDCl₃): 2.40(3H, s), 2.67(3H, s), 5.58(2H, s), 6.38(2H, t, J=2Hz), 6.92(1H, d, J=8 Hz), 7.10(2H, t, J=2 Hz), 7.24-7.30(3H, m),7.54(1H, d, J=2 Hz), 7.94-7.98(2H, m), 8.04-8.09(2H, m), 10.05(1H, s).MASS(ESI): m/z 518(M−H)⁻. m.p. 178-180° C.

EXAMPLE 85

To a solution of3-[2-chloro-4-(cyclohexylmethyloxy)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(50 mg) in N,N-dimethylformamide (0.25 ml) was added dropwise 1N aqueoussodium hydroxide solution (0.2 ml) at 80° C. Heating was immediatelystopped and the mixture was stirred at room temperature. After 1 hr, theprecipitated crystals were collected by filtration and washed 3 timeswith N,N-dimethylformamide:water=5:4 (0.5 ml) and 3 times with water(0.5 ml). The crystals were dried under reduced pressure at 50° C. for 5hr to give3-[2-chloro-4-(cyclohexylmethyloxy)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinesodium salt as colorless crystals (40 mg).

¹H-NMR(CDCl₃): 0.88(3H, t, J=7 Hz), 0.95-1.90(17H, m), 2.34(3H, s),2.55(2h, br t, J=7 Hz), 3.67-3.70(2H, m), 5.41-5.61(2H, m), 6.30(1H, dd,J=8, 2 Hz), 6.58(1H, d, J=8 Hz), 6.83(1H, d, J=8 Hz), 7.81(1H, d, J=8Hz), 8.06(1H, d, J=8 Hz). MASS(ESI): m/z 545(M−Na)⁻. m.p. >250° C.

Results:

3-[2-Chloro-4-(cyclohexylmethyloxy)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinesodium salt showed markedly improved oral absorption as compared to3-[2-chloro-4-(cyclohexylmethyloxy)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,which fact was demonstrated by C_(max) that was 2 to 3 times greater inrats and about 16 times greater in dogs.

EXAMPLE 86

In the same manner as in Example 1,3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (212 mg) from3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 1-pentanesulfonamide (120 mg).

¹H-NMR(CDCl₃): 0.85(3H, t, J=8 Hz), 1.22-1.46(4H, m), 1.77-1.90(2H, m),2.65(3H, s), 2.74(3H, s), 3.48-3.56(2H, m), 5.56(2H, s), 6.48(1H, m),6.70(1H, d, J=5 Hz), 6.76(1H, d, J=8 Hz), 7.43-7.50(2H, m), 7.77(1H, d,J=1 Hz), 8.01(1H, s), 9.86(1H, br s). MASS(ESI): m/z 513(M−1). m.p.177-178° C.

EXAMPLE 87

In the same manner as in Example 1,3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (212 mg) from3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and p-toluenesulfonamide (140 mg).

¹H-NMR(CDCl₃): 2.39(3H, s), 2.64(3H, s), 2.67(3H, s), 5.56(2H, s),6.50(1H, m), 6.72(1H, d, J=5 Hz), 6.80(1H, d, J=8 Hz), 7.26(2H, d, J=8Hz), 7.47-7.54(2H, m), 7.78(1H, d, J=1 Hz), 7.89(1H, s), 7.99(2H, d, J=8Hz), 10.12(1H, br s). MASS(ESI): m/z 533(M−1). m.p. 189-190° C.

EXAMPLE 88

In the same manner as in Example 1,3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-5-(1-butanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (213 mg) from3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 1-butanesulfonamide (112 mg).

¹H-NMR(CDCl₃): 0.90(3H, t, J=8 Hz), 1.36-1.51(2H, m), 1.75-1.89(2H, m),2.65(3H, s), 2.74(3H, s), 3.49-3.58(2H, m), 5.56(2H, s), 6.48(1H, m),6.70(1H, d, J=5 Hz), 6.77(1H, d, J=8 Hz), 7.44-7.50(2H, m), 7.77(1H, d,J=1 Hz), 8.01(1H, s), 9.86(1H, br s). MASS(ESI): m/z 499(M−1). m.p.231-233° C.

EXAMPLE 89

In the same manner as in Example 1,3-(2,4-dichloro-5-nitrobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (59 mg) from3-[(2,4-dichloro-5-nitro)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (170 mg) and 1-pentanesulfonamide (101 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=8 Hz), 1.24-1.50(4H, m), 1.82-1.95(2H, m),2.65(3H, s), 3.53-3.61(2H, m), 5.60(2H, s), 7.21(1H, s), 7.77(1H, s),8.19(1H, d, J=8 Hz), 8.27(1H, d, J=8 Hz), 9.74(1H, br s). MASS(ESI): m/z514(M−1).

EXAMPLE 90

In the same manner as in Example 1,3-(2,4-dichloro-5-nitrobenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (205 mg) from3-[(2,4-dichloro-5-nitro)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (170 mg) and 4-methylbenzenesulfonamide (115 mg).

¹H-NMR(CDCl₃): 2.43(3H, s), 2.62(3H, s), 5.61(2H, s), 7.23(1H, s),7.34(2H, d, J=8 Hz), 7.77(1H, s), 8.03(2H, d, J=8 Hz), 8.11(1H, d, J=8Hz), 8.15(1H, d, J=8 Hz), 10.09(1H, br s). MASS(ESI): m/z 534(M−1).

EXAMPLE 91

In the same manner as in Example 1,3-[2,4-dichloro-5-(N,N-dimethylamino)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (174 mg) from3-[2,4-dichloro-5-(N,N-dimethylamino)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (190 mg) and 1-pentanesulfonamide (114 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=8 Hz), 1.27-1.50(4H, m), 1.84-1.96(2H, m),2.59(6H, s), 2.63(3H, s), 3.52-3.62(2H, m), 5.54(2H, s), 6.33(1H, s),7.47(1H, s), 8.15(1H, d, J=8 Hz), 8.24(1H, d, J=8 Hz), 9.90(1H, br s).MASS(ESI): m/z 510(M−1).

EXAMPLE 92

In the same manner as in Example 1,3-[2,4-dichloro-5-(N,N-dimethylamino)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (213 mg) from3-[2,4-dichloro-5-(N,N-dimethylamino)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (190 mg) and 4-methylbenzenesulfonamide (129 mg).

¹H-NMR(CDCl₃): 2.43(3H, s), 2.57(6H, s), 2.62(3H, s), 5.55(2H, s),6.34(1H, s), 7.35(2H, d, J=8 Hz), 7.49(1H, s), 8.04-8.15(4H, m),10.17(1H, br s). MASS(ESI): m/z 530(M−1).

EXAMPLE 93

3-(2-Chloro-4-(methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(220 mg) was dissolved in dichloromethane (200 ml), and pyridine (196mg) and 1-butanesulfonyl chloride (453 mg) were added, which wasfollowed by refluxing under heating for 12 hr. The reaction mixture wasconcentrated under reduced pressure, and water and 1N hydrochloric acidwere added to adjust to pH 4. The mixture was extracted with chloroform.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel thin layer chromatography(chloroform:methanol=19:1) and ethanol (5 ml) was added to the purifiedproduct. The precipitated crystals were collected by filtration. Thecrystals were dissolved in N,N-dimethylformamide (1 ml) and water (0.85ml) was added on an oil bath at 80° C. The mixture was allowed to cooland the precipitated crystals were collected by filtration to give3-(4-(N-(1-butanesulfonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(38 mg) as pale-yellow crystals.

¹H-NMR(CDCl₃): 0.92(3H, t, J=7 Hz), 1.37-1.50(2H, m), 1.74-1.85(2H, m),2.43(3H, s), 2.64(3H, s), 3.02(2H, t, J=7 Hz), 3.35(3H, s), 5.57(2H, s),6.72(1H, d, J=8 Hz), 7.25(1H, dd, J=8, 2 Hz), 7.35(2H, d, J=8 Hz),7.56(1H, d, J=2 Hz), 8.04-8.12(4H, m), 10.05(1H, s). MASS(ESI): m/z602(M−H)⁻. m.p. 158-159° C.

EXAMPLE 94

In the same manner as in Example 85,3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinesodium salt (175 mg) was obtained as colorless crystals from3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(233 mg).

¹H-NMR(DMSO-d₆): 0.83(3H, t, J=7 Hz), 1.22-1.32(4H, m), 1.38(9H, s),1.52-1.64(2H, m), 2.46(3H, s), 3.05(2H, t, J=7 Hz), 3.15(3H, s),5.56(2H, s), 6.43(1H, d, J=8 Hz), 7.14(1H, dd, J=8, 2 Hz), 7.54(1H, d,J=2 Hz), 7.83(1H, d, J=8 Hz), 7.98(1H, d, J=8 Hz) MASS(ESI): m/z562(M−H)⁻. m.p. 231-233° C.

EXAMPLE 95

In the same manner as in Example 65,3-(2-chloro-4-(N-methyl-N-(1-propoxycarbonyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(175 mg) was obtained as colorless crystals from3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(299 mg) and 1-propyl chlorocarbonate (87 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 0.91(3H, t, J=7 Hz), 1.27-1.48(4H,m), 1.60-1.72(2H, m), 1.85-1.95(2H, m), 2.64(3H, s), 3.30(3H, s),3.57(2H, t, J=7 Hz), 4.09(2H, t, J=7 Hz), 5.56(2H, s), 6.66(1H, d, J=8Hz), 7.12(1H, dd, J=8, 2 Hz), 7.47(1H, d, J=2 Hz), 8.14(1H, d, J=8 Hz),8.21(1H, d, J=8 Hz), 9.84(1H, s). MASS(ESI): m/z 548(M−H)⁻. m.p.169-170° C.

EXAMPLE 96

In the same manner as in Example 65,3-(2-chloro-4-(N-methyl-N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(173 mg) was obtained as colorless crystals from3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(299 mg) and isopropyl chlorocarbonate (87 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.25(6H, d, J=7 Hz), 1.31-1.48(4H,m), 1.84-1.95(2H, m), 2.64(3H, s), 3.29(3H, s), 3.57(2H, t, J=7 Hz),4.90-5.03(1H, m), 5.56(2H, s), 6.65(1H, d, J=8 Hz), 7.11(1H, dd, J=8, 2Hz), 7.46(1H, d, J=2 Hz), 8.14(1H, d, J=8 Hz), 8.21(1H, d, J=8 Hz),9.84(1H, s). MASS(ESI): m/z 548(M−H)⁻. m.p. 151-152° C.

EXAMPLE 97

In the same manner as in Example 1,3-(4-(N-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(217 mg) was obtained as pale-yellow crystals from3-(4-(N-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (234 mg) and 1-pentanesulfonamide (127 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.27-1.48(4H, m), 1.50(9H, s),1.83-1.94(2H, m), 2.64(3H, s), 3.55(2H, t, J=7 Hz), 5.51(2H, s),6.58(1H, s), 6.77(1H, d, J=8 Hz), 7.03(1H, dd, J=8, 2 Hz), 7.77(1H, s),8.11(1H, d, J=8 Hz), 7.18(1H, d, J=8 Hz), 9.79(1H, s). MASS(ESI): m/z548(M−H)⁻. m.p. 222-224° C.

EXAMPLE 98

In the same manner as in Example 1,3-(2-chloro-4-(ethoxycarbonylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as thin yellow crystals (191 mg) from3-(2-chloro-4-(ethoxycarbonylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (250 mg) and 1-pentanesulfonamide (146 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.24-1.50(4H, m), 1.31(3H, t, J=7Hz), 1.81-1.95(2H, m), 2.65(3H, s), 3.50-3.60(2H, m), 4.22(2H, q, J=7Hz), 5.52(2H, s), 6.79(1H, d, J=8 Hz), 7.11(1H, dd, J=1, 8 Hz), 7.74(1H,d, J=1 Hz), 8.11(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz). MASS(ESI): m/z520(M−1).

EXAMPLE 99

In the same manner as in Example 1,3-(2-chloro-4-(N-valerylamino)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as thin yellow crystals (196 mg) from3-(2-chloro-4-(N-valerylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and (4-methylbenzene)sulfonamide (128 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.33-1.48(2H, m), 1.65-1.77(2H, m),2.37(2H, t, J=7 Hz), 2.42(3H, s), 2.65(3H, s), 5.52(2H, s), 6.85(1H, d,J=8 Hz), 7.20-7.29(2H, m), 7.34(2H, d, J=8 Hz), 7.95-8.09(4H, m).MASS(ESI): m/z 552(M−1).

EXAMPLE 100

In the same manner as in Example 1,3-(4-(N-(1-butanesulfonyl)amino)-2-chlorobenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as thin ochroid crystals (201 mg) from3-(4-(N-(1-butanesulfonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (200 mg) and 4-methylbenzenesulfonamide (118 mg).

¹H-NMR(CDCl₃): 0.91(3H, t, J=7 Hz), 1.37-1.51(2H, m), 1.75-1.89(2H, m),2.43(3H, s), 2.65(3H, s), 3.11-3.20(2H, m), 5.52(2H, s), 6.80(1H, d, J=8Hz), 7.04(1H, dd, J=1, 8 Hz), 7.35(2H, d, J=8 Hz), 7.42(1H, d, J=1 Hz),8.00-8.12(4H, m). MASS(ESI): m/z 588(M−1).

EXAMPLE 101

In the same manner as in Example 1,3-(2-chloro-4-(N-(t-butylacetyl)amino)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as thin yellow crystals (204 mg) from3-(2-chloro-4-(N-(t-butylacetyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (240 mg) and 4-methylbenzenesulfonamide (149 mg).

¹H-NMR(CDCl₃): 1.10(9H, s), 2.23(2H, s), 2.42(3H, s), 2.65(3H, s),5.52(2H, s), 6.83(1H, d, J=8 Hz), 7.18-7.28(2H, m), 7.34(2H, d, J=8 Hz),7.95-8.09(4H, m). MASS(ESI): m/z 566(M−1).

EXAMPLE 102

In the same manner as in Example 1,3-(2-chloro-4-(N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (39 mg) from3-(2-chloro-4-(N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (79 mg) and (E)-1-penten-1-ylsulfonamide (44 mg).

¹H-NMR(CDCl₃): 0.95(3H, t, J=7 Hz), 1.29(6H, d, J=7 Hz), 1.47-1.63(2H,m), 2.22-2.33(2H, m), 2.64(3H, s), 4.95-5.05(1H, m), 5.52(2H, s),6.58(1H, d, J=16 Hz), 6.75(1H, d, J=8 Hz), 7.05-7.20(2H, m), 7.75(1H,s), 8.09(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz). MS(ESI): m/z 532(M−1).m.p. 187-189° C.

EXAMPLE 103

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (53 mg) from3-(2-chloro-4-(N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (79 mg) and 1-butanesulfonamide (40 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.29(6H, d, J=7 Hz), 1.40-1.56(2H,m), 1.80-1.91(2H, m), 2.65(3H, s), 3.51-3.60(2H, m), 4.95-5.05(1H, m),5.52(2H, s), 6.79(1H, d, J=8 Hz), 7.10(1H, dd, J=1, 8 Hz), 7.75(1H, s),8.10(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz). MS(ESI): m/z 520(M−1). m.p.181-182° C.

EXAMPLE 104

3-(2-Chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (150 mg) was dissolved in dry N,N-dimethylformamide (1.5 ml), andcarbonyldiimidazole (91 mg) was added, which was followed by stirring atroom temperature for 1.5 hr. To the reaction mixture was added1-penten-1-ylsulfonamide sodium salt (96 mg) and the mixture was stirredat room temperature for 7 hr. 1N Hydrochloric acid was added dropwiseunder ice-cooling to adjust to pH 4. Water (1.5 ml) was added and themixture was applied to ultrasonic washer for 15 min and then stirred for15 min. The precipitate was collected by filtration, washed with water,suspended in ethanol (0.5 ml), heated in a boiling bath and stirred atroom temperature for 30 min. The precipitate was collected byfiltration, washed with ethanol, and recrystallized fromN,N-dimethylformamide and water to give3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(165 mg) as colorless crystals.

m.p.: 165-166° C. ¹H-NMR(CDCl₃): 0.95(3H, t, J=6 Hz), 1.27(3H, t, J=6Hz), 1.55(2H, m), 2.29(2H, q, J=6 Hz), 2.65(3H, s), 3.30(3H, s),4.19(2H, q, J=6 Hz), 5.55(2H, s), 6.56-6.66(2H), 7.07-7.20(2H), 7.46(1H,d, J=2 Hz), 8.12(1H, d, J=8 Hz), 8.19(1H, d, J=8 Hz), 9.91(1H, br. s).MS(ESI): m/z 535(M+1)

EXAMPLE 105

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine(110 mg) was obtained as colorless crystals from3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (128 mg).

m.p.: 169-170° C. ¹H-NMR(CDCl₃): 0.95(3H, t, J=6 Hz), 1.26(3H, t, J=6Hz), 1.49(2H, m), 1.88(2H, m), 2.65(3H, s), 3.30(3H, s), 3.58(2H, t, J=6Hz), 4.19(2H, q, J=6 Hz), 5.55(2H, s), 6.65(1H, d, J=8 Hz), 7.11(1H, dd,J=8, 2 Hz), 7.46(1H, d, J=2 Hz), 8.14(1H, d, J=8 Hz), 8.21(1H, d, J=8Hz), 9.82(1H, br. s). MS(ESI): m/z 523(M+1)

EXAMPLE 106

In the same manner as in Example 42,3-(4-amino-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(284 mg) was obtained as pale-yellow crystals from3-(4-(N-t-butoxycarbonylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(390 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.30-1.50(4H, m), 1.85-1.95(2H, m),2.67(3H, s), 3.56(2H,t, J=7 Hz), 3.83(2H, s), 5.45(2H, s), 6.53(1H, dd,J=8, 2 Hz), 6.72-6.75(2H, m), 8.08(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz),9.84(1H, s)

EXAMPLE 107

In the same manner as in Example 65,3-(4-N-(1-propoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(125 mg) was obtained as colorless crystals from3-(4-amino-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(130 mg) and n-propyl chlorocarbonate (39 mg).

¹H-NMR(CDCl₃): 0.88(3H, t, J=7 Hz), 0.97(3H, t, J=7 Hz), 1.30-1.48(4H,m), 1.64-1.76(2H, m), 1.83-1.93(2H, m), 2.65(3H, s), 3.55(2H, t, J=7Hz), 4.12(2H, t, J=7 Hz), 5.52(2H, s), 6.74(1H, s), 6.78(1H, d, J=8 Hz),7.12(1H, dd, J=8, 2 Hz), 7.75(1H, d, J=2 Hz), 8.11(1H, d, J=8 Hz),8.18(1H, d, J=8 Hz), 9.78(1H, s) Mass(ESI): m/z 534(M−H)⁻ m.p. 215-216°C.

EXAMPLE 108

In the same manner as in Example 65,3-(4-(N-(isopropoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(120 mg) was obtained as pale-yellow crystals from3-(4-amino-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(130 mg) and isopropyl chlorocarbonate (39 mg).

¹H-NMR(CDCl₃): 0.88(3H, t, J=7 Hz), 1.29(6H, d, J=7 Hz), 1.32-1.46(4H,m), 1.83-1.93(2H, m), 2.65(3H, s), 3.55(2H, t, J=7 Hz), 4.94-5.06(1H,m), 5.52(2H, s), 6.67(1H, s), 6.78(1H, d, J=8 Hz), 7.11(1H, dd, J=8, 2Hz), 7.75(1H, d, J=2 Hz), 8.11(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz),9.78(1H, s) Mass(ESI): m/z 534(M−H)⁻ m.p. 198-199° C.

EXAMPLE 109

In the same manner as in Example 1,5-(1-butanesulfonylcarbamoyl)-3-(4-(N-t-butoxycarbonylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine(270 mg) was obtained as pale-yellow crystals from3-(4-(N-t-butoxycarbonylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (300 mg) and 1-butanesulfonamide. (148 mg).

¹H-NMR(CDCl₃): 0.94(3H, t, J=7 Hz), 1.42-1.55(2H, m), 1.50(9H, s),1.81-1.92(2H, m), 2.65(3H, s), 3.56(2H, t, J=7 Hz), 5.52(2H, s),6.59(1H, s), 6.77(1H, d, J=8 Hz), 7.03(1H, dd, J=8, 2 Hz), 7.78(1H, s),8.11(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz), 9.78(1H, s) Mass(ESI): m/z534(M−H)⁻ m.p. 229-230° C.

EXAMPLE 110

In the same manner as in Example 42,3-(4-amino-2-chlorobenzyl)-5-(1-butanesulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine(124 mg) was obtained as pale-yellow crystals from5-(1-butanesulfonylcarbamoyl)-3-(4-(N-t-butoxycarbonylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine(207 mg).

¹H-NMR(CDCl₃): 0.95(3H, t, J=7 Hz), 1.43-1.56(2H, m), 1.82-1.92(2H, m),2.67(3H, s), 3.57(2H, t, J=7 Hz), 3.83(2H, s), 5.45(2H, s), 6.52(1H, dd,J=8, 2 Hz), 6.73-6.76(2H, m), 8.08(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz),9.82(1H, s)

EXAMPLE 111

In the same manner as in Example 65,3-(4-ethoxycarbonylamino-2-chlorobenzyl)-2-methyl-5-(1-butanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(100 mg) was obtained as colorless crystals from3-(4-amino-2-chlorobenzyl)-5-(1-butanesulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine(102 mg) and ethyl chlorocarbonate (28 mg).

¹H-NMR(CDCl₃—CD₃OD): 0.94(3H, t, J=7 Hz), 1.30(3H, t, J=7 Hz),1.42-1.55(2H, m), 1.80-1.90(2H, m), 2.53(1H, s), 2.66(3H, s), 3.56(2H,t, J=7 Hz), 4.21(2H, q, J=7 Hz), 5.53(2H, s), 6.82(1H, d, J=8 Hz),7.16(1H, dd, J=8, 2 Hz), 7.73(1H, s), 8.11(1H, d, J=8 Hz), 8.18(1H, d,J=8 Hz) Mass(ESI): m/z 506(M−H)⁻ m.p. 236-237° C.

EXAMPLE 112

In the same manner as in Example 1,3-(4-(N-t-butoxy-carbonylamino)-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(181 mg) was obtained as pale-yellow crystals from3-(4-(N-t-butoxycarbonylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (300 mg) and (E)-1-penten-1-ylsulfonamide (161 mg).

¹H-NMR(CDCl₃): 0.95(3H, t, J=7 Hz), 1.51(9H, s), 1.50-1.60(2H, m),2.28(2H, q, J=7 Hz), 2.63(3H, s), 5.51(2H, s), 6.56-6.62(2H, m),6.72(1H, d, J=8 Hz), 7.03(1H, dd, J=8, 2 Hz), 7.08-7.19(1H, m), 7.76(1H,d, J=2 Hz), 8.08(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz), 9.87(1H, s)Mass(ESI): m/z 546(M−H)⁻ m.p. 215-216° C.

EXAMPLE 113

In the same manner as in Example 42,3-(4-amino-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(170 mg) was obtained as pale-yellow crystals from3-(4-(N-t-butoxycarbonylamino)-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(253 mg).

¹H-NMR(CDCl₃): 0.96(3H, t, J=7 Hz), 1.48-1.60(2H, m), 2.28(2H, q, J=7Hz), 2.66(3H, s), 3.84(2H, s), 5.45(2H, s), 6.52(1H, dd, J=8, 2 Hz),6.60(1H, d, J=16 Hz), 6.71(1H, d, J=8 Hz), 6.76(1H, d, J=2 Hz),7.09-7.19(1H, m), 8.07(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz), 9.92(1H, s)

EXAMPLE 114

In the same manner as in Example 65,3-(4-ethoxycarbonyl-amino-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(122 mg) was obtained as colorless crystals from3-(4-amino-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(130 mg) and ethyl chlorocarbonate (35 mg).

¹H-NMR(CDCl₃): 0.95(3H, t, J=7 Hz), 1.31(3H, t, J=7 Hz), 1.48-1.60(2H,m), 2.28(2H, q, J=7 Hz), 2.64(3H, s), 4.23(2H, q, J=7 Hz), 5.52(2H, s),6.58(1H, d, J=16 Hz), 6.72(1H, s), 6.75(1H, d, J=8 Hz), 7.10-7.19(2H,m), 7.74(1H, d, J=2 Hz), 8.09(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz),9.86(1H, s) Mass(ESI): m/z 518(M−H)⁻ m.p. 233-234° C.

EXAMPLE 115

In the same manner as in Example 104,3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(190 mg) was obtained as colorless crystals from3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (164 mg).

m.p.: 154-155° C. ¹H-NMR(CDCl₃): 0.95(3H, t, J=6 Hz), 1.46(9H, s),1.55(2H, m), 2.28(2H, q, J=6 Hz), 2.63(3H, s), 3.25(3H, s), 5.55(2H, s),6.55-6.65(2H), 7.07-7.22(2H), 7.46(1H, d, J=2 Hz), 8.12(1H, d, J=8 Hz),8.19(1H, d, J=8 Hz), 9.91(1H, br. s). MS(ESI): m/z 561(M−1)

EXAMPLE 116

In the same manner as in Example 1,3-(2-chloro-4-(3-(1-propyl)ureido)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as thin yellow crystals (126 mg) from3-(2-chloro-4-(3-(1-propyl)ureido)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (130 mg) and (4-methylbenzene)sulfonamide (83 mg).

¹H-NMR(DMSO-d₆): 0.86(3H, t, J=7 Hz), 1.36-1.50(2H, m), 2.39(3H, s),2.47(3H, s), 2.99-3.10(2H, m), 5.73(2H, s), 6.72(1H, d, J=8 Hz),7.05(1H, dd, J=1, 8 Hz), 7.43(2H, d, J=8 Hz), 7.84-7.97(4H, m), 8.11(1H,d, J=8 Hz). MS(ESI): m/z 553(M−1) m.p. 263-265° C.

EXAMPLE 117

3-(2-Chloro-4-(methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(300 mg) was suspended in toluene (6 ml) and n-propyl isocyanate (264mg) was added at room temperature, which was followed by stirring at 90°C. for 5 hr. The reaction mixture was concentrated under reducedpressure and ethanol (6 ml) was added to the residue. The mixture washeated and allowed to cool, and the precipitated crystals were collectedby filtration. The crystals were dissolved in N,N-dimethylformamide (3.5ml) and hot water (4.0 ml) was gradually added on an oil bath at 80° C.While stirring for 1 hr, the reaction mixture was allowed to cool, andthe precipitated crystals were collected by filtration and dried byheating under reduced pressure to give3-(4-(1-methyl-3-(1-propyl)ureido)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(309 mg) as colorless crystals.

¹H-NMR(CDCl₃): 0.86(3H, t, J=7 Hz), 1.42-1.54(2H, m), 2.43(3H, s),2.63(3H, s), 3.17(2H, q, J=7 Hz), 3.27(3H, s), 4.46(1H, t, J=7 Hz),5.58(2H, s), 6.66(1H, d, J=8 Hz), 7.10(1H, dd, J=8, 2 Hz), 7.35(2H, d,J=8 Hz), 7.45(1H, d, J=2 Hz), 8.03-8.14(4H, m), 10.12(1H, s) Mass(ESI):m/z 567(M−H)⁻. m.p. 190-191° C.

EXAMPLE 118

In the same manner as in Example 1,3-(2-chloro-4-(2-oxo-1-pyrrolidinyl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(194 mg) was obtained as pale-yellow crystals from3-(2-chloro-4-(2-oxotetrahydro-1H-pyrrol-1-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (173 mg) and (4-methylbenzene)sulfonamide (115 mg).

¹H-NMR(CDCl₃): 2.13-2.24(2H, m), 2.42(3H, s), 2.60-2.65(5H, m), 3.87(2H,t, J=7 Hz), 5.55(2H, s), 6.82(1H, d, J=8 Hz),7.33(2H, d, J=8 Hz),7.45(1H, dd, J=8, 2 Hz), 7.96(1H, d, J=2 Hz), 8.01-8.08(4H, m),10.07(1H, s) Mass(ESI): m/z 536(M−H)⁻. m.p. 242-243° C.

EXAMPLE 119

In the same manner as in Example 1,3-(2-chloro-4-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(158 mg) was obtained as pale-yellow crystals and3-(2-chloro-4-(((2-(4-methylbenzene)sulfonylcarbamoyloxy)ethyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(37 mg) as a yellow powder, from a mixture of3-(2-chloro-4-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid and methyl3-(2-chloro-4-((2-hydroxyethyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate,and (4-methylbenzene)sulfonamide (282 mg).3-(2-chloro-4-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine

¹H-NMR(CDCl₃): 2.42(3H, s), 2.66(3H, s), 4.09(2H, t, J=7 Hz), 4.51(2H,t, J=7 Hz), 5.54(2H, s), 6.92(1H, d, J=8 Hz), 7.34-7.47(3H, m), 7.89(1H,d, J=2 Hz), 8.00-8.07(4H, m), 10.03(1H, s) Mass(ESI): m/z 538(M−H)⁻.m.p. 243-245° C.

3-(2-chloro-4-(((2-(4-methylbenzene)sulfonylcarbamoyloxy)ethyl)-amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine

¹H-NMR(CDCl₃): 2.40(3H, s), 2.43(3H, s), 2.67(3H, s), 3.30(2H, t, J=7Hz), 3.67(1H, t, J=7 Hz), 4.21(2H, t, J=7 Hz), 5.47(2H, s), 6.48(1H, dd,J=8, 2 Hz), 6.63(1H, d, J=2 Hz), 6.81(1H, d, J=8 Hz), 7.27-7.37(4H, m),7.85(2H, d, J=8 Hz), 7.98-8.05(4H, m) Mass(ESI): m/z 709(M−H)⁻

EXAMPLE 120

In the same manner as in Example 1,3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(69 mg) was obtained as pale-yellow crystals from3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (100 mg) and 1-pentanesulfonamide (245 mg).

m.p. 229-231° C. ¹H-NMR(CDCl₃): 0.88(3H, t, J=7 Hz), 1.24-1.49(4H, m),1.79-1.93(2H, m), 2.65(3H, s), 2.68(3H, s), 3.49-3.59(2H, m), 3.74(3H,s), 5.71(2H, s), 6.96(1H, d, J=8 Hz), 7.23(1H, d, J=8 Hz), 8.08(1H, d,J=8 Hz), 8.15(1H, d, J=8 Hz), 9.70(1H, br s). MASS(ESI): m/z 501(M−1)

EXAMPLE 121

In the same manner as in Example 1,3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine(76 mg) was obtained as pale-yellow crystals from3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (100 mg) and (4-methylbenzene)sulfonamide (278 mg).

m.p. >250° C. ¹H-NMR(CDCl₃): 2.42(3H, s), 2.66(3H, s), 2.67(3H, s),3.76(3H, s), 5.72(2H, s), 6.96(1H, d, J=8 Hz), 7.25(1H, d, J=8 Hz),7.32(2H, d, J=8 Hz), 7.95-8.04(4H, m), 10.00(1H, br s). MASS(ESI): m/z521(M−1).

EXAMPLE 122

In the same manner as in Example 1,3-((6-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (22 mg) from 3-((6-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (60 mg) and (4-methylbenzene)sulfonamide (42 mg).

¹H-NMR(CDCl₃): 2.41(3H, s), 2.56(3H, s), 2.59(3H, s), 3.74(3H, s),5.68(2H, s), 6.88(1H, s), 7.32(2H, d, J=8 Hz), 7.48(1H, s), 8.01(2H, d,J=8 Hz), 8.05(2H, d, J=1 Hz). MS(ESI): m/z 521(M−1). m.p. 279-280° C.

EXAMPLE 123

In the same manner as in Example 1,3-[(3,5-dichloro-pyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (165 mg) from3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (160 mg) and 1-pentanesulfonamide (108 mg).

m.p. 155-156° C. ¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.24-1.50(4H, m),1.82-1.96(2H, m), 2.70(3H, s), 3.51-3.61(2H, m), 5.67(2H, s), 7.82(1H,d, J=1 Hz), 8.10(1H, d, J=8 Hz), 8.17(1H, d, J=8 Hz), 8.29(1H, d, J=1Hz), 9.93(1H, br s). MASS(ESI): m/z 468(M−1).

EXAMPLE 124

In the same manner as in Example 1,3-[(3,5-dichloro-pyridin-2-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as a colorless solid (175 mg) from3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (160 mg) and (4-methylbenzene)sulfonamide (122 mg).

m.p. 197-199° C. ¹H-NMR(CDCl₃): 2.43(3H, s), 2.67(3H, s), 5.67(2H, s),7.34(2H, d, J=8 Hz), 7.85(1H, d, J=1 Hz), 7.99-8.09(4H, m), 8.30(1H, d,J=8 Hz), 10.20(1H, br s). MASS(ESI): m/z 488(M−1).

EXAMPLE 125

In the same manner as in Example 1,3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-5-((4-methylbenzene-sulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine(114 mg) was obtained as colorless crystals from3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (102 mg) and (4-methylbenzene)sulfonamide (75 mg).

m.p. 235-236° C. ¹H-NMR(CDCl₃): 2.41(3H, s), 2.66(3H, s), 2.68(3H, s),5.64(2H, s), 7.33 (2H, d, J=8 Hz), 7.83(1H, d, J=1 Hz), 7.86(1H, s),8.04(2H, d, J=8 Hz), 8.30(1H, d, J=1 Hz). MS(ESI): m/z 503(M−1).

EXAMPLE 126

In the same manner as in Example 1,3-((3,5-dichloro-pyridin-2-yl)methyl)-2,7-dimethyl-5-(((E)-2-phenylethene-sulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine(113 mg) was obtained as colorless crystals from3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (102 mg) and (E)-2-phenylethenesulfonamide (75 mg).

m.p. 219-220° C. ¹H-NMR(CDCl₃): 2.67(3H, s), 2.70(3H, s), 5.64(2H, s),7.14(1H, d, J=16 Hz), 7.36-7.57(5H), 7.76-7.84(2H), 7.95(1H, s),8.28(1H, d, J=1 Hz). MS(ESI) m/z 515(M−1)

EXAMPLE 127

In the same manner as in Example 1,3-[(2-chloro-6-phenylpyridin-3-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (206 mg) from3-[(2-chloro-6-phenylpyridin-3-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (180 mg) and 1-pentanesulfonamide (108 mg).

m.p. 224-225° C. ¹H-NMR(CDCl₃): 0.85(3H, t, J=7 Hz), 1.20-1.45(4H, m),1.86-1.90(2H, m), 2.70(3H, s), 3.49-3.57(2H, m), 5.61(2H, s), 7.20(1H,d, J=8 Hz), 7.40-7.51(3H, m), 7.65(1H, d, J=8 Hz), 7.96-8.04(2H, m),8.15(1H, d, J=8 Hz), 8.22(1H, d, J=8 Hz), 9.76(1H, br s). MASS(ESI): m/z510(M−1).

EXAMPLE 128

In the same manner as in Example 1,3-[(2-chloro-6-phenylpyridin-3-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (210 mg) from3-[(2-chloro-6-phenylpyridin-3-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (180 mg) and (4-methylbenzene)sulfonamide (122 mg).

m.p. 236-238° C. ¹H-NMR(CDCl₃): 2.38(3H, s), 2.69(3H, s), 5.61(2H, s),7.21-7.28(3H, m), 7.43-7.53(3H, m), 7.69(1H, d, J=8 Hz), 7.94-8.14(6H,m), 10.04(1H, br s). MASS(ESI): m/z 530(M−1).

EXAMPLE 129

In the same manner as in Example 1,3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (126 mg) from3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (128 mg) and 1-pentanesulfonamide (70 mg).

m.p. 193-194° C. ¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.25-1.50(4H, m),1.51(9H, s), 1.84-1.96(2H, m), 2.72(3H, s), 3.51-3.59(2H, m), 5.63(2H,s), 6.65(1H, br s), 7.06(1H, d, J=8 Hz), 8.09-8.15(2H,m), 8.25(1H, brs), 9.55(1H, br s). MASS(ESI): m/z 549(M−1).

EXAMPLE 130

In the same manner as in Example 104,3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as pale-brown crystals (133 mg) from3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (128 mg) and (E)-1-penten-1-ylsulfonamide sodium salt (79 mg).

m.p. 202-204° C. ¹H-NMR(CDCl₃): 0.95(3H, t, J=7 Hz), 1.47-1.61(11H, m),2.23-2.33(2H, m), 2.70(3H, s), 5.62(2H, s), 6.59(1H, d, J=15 Hz),6.67(1H, br s), 7.15(1H, dt, J=15, 7 Hz), 8.04(1H, d, J=8 Hz),8.08-8.13(2H, m), 8.26(1H, br s), 10.03(1H, br s). MASS(ESI): m/z547(M−1).

EXAMPLE 131

In the same manner as in Example 1,3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as pale-brown crystals (119 mg) from3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (128 mg) and (4-methylbenzene)sulfonamide (79 mg).

m.p. 163-165° C. ¹H-NMR(CDCl₃): 1.52(9H, s), 2.42(3H, s), 2.71(3H, s),5.63(2H, s), 6.67(1H, br s), 7.34(2H, d, J=8 Hz),7.96-8.09(4H, m),8.13(1H, d, J=1 Hz), 8.30(1H, br s). MASS(ESI): m/z 569(M−1).

EXAMPLE 132

In the same manner as in Example 1,3-[(3-chloro-5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (75 mg) from3-[3-chloro(5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (78 mg) and 1-pentanesulfonamide (47 mg).

m.p. 232-233° C. ¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.24-1.50(7H, m),1.83-1.96(2H, m), 2.72(3H, s), 3.50-3.59(2H, m), 4.24(2H, q, J=7 Hz),5.63(2H, s), 6.84(1H, br s), 8.06(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz),8.18(1H, d, J=2 Hz), 8.24(1H, br s), 9.92(1H, br s). MASS(ESI): m/z521(M−1).

EXAMPLE 133

In the same manner as in Example 104,3-[(3-chloro-5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (84 mg) from3-[(3-chloro-5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (78 mg) and (E)-1-penten-1-ylsulfonamide sodium salt (53 mg).

m.p. 236-239° C. ¹H-NMR(CDCl₃): 0.95(3H, t, J=7 Hz), 1.32(3H, t, J=7Hz), 1.54(2H, q, J=7 Hz), 2.22-2.33(2H, m), 2.71(3H, s), 4.24(2H, q, J=7Hz), 5.63(2H, s), 6.58(1H, d, J=15 Hz), 6.86(1H, br s), 7.14(1H, dt,J=15, 7 Hz), 8.04(1H, d, J=8 Hz), 8.10(1H, d, J=8 Hz), 8.17(1H, d, J=2Hz), 8.24(1H, br s), 10.01(1H, br s). MASS(ESI): m/z 519(M−1).

EXAMPLE 134

In the same manner as in Example 1,3-[(3-chloro-5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (71 mg) from3-[3-chloro(5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (78 mg) and (4-methylbenzene)sulfonamide (53 mg).

m.p. 244-246° C. ¹H-NMR(CDCl₃): 1.32(3H, t, J=7 Hz), 2.42(3H, s),2.71(3H, s), 4.25(2H, q, J=7 Hz), 5.64(2H, s), 6.87(1H, br s), 7.33(2H,d, J=8 Hz), 7.96-8.08(4H, m), 8.19(1H, d, J=2 Hz), 8.26(1H, br s).MASS(ESI): m/z 541(M−1).

EXAMPLE 135

In the same manner as in Example 1,3-[(5-(N-(isopropoxy-carbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (82 mg) from3-[(5-(N-(isopropoxycarbonyl)-amino)-3-chloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (90 mg) and 1-pentanesulfonamide (51 mg).

¹H-NMR(DMSO-d₆): 0.79(3H, t, J=7 Hz), 1.16-1.40(4H, m), 1.24(6H, d, J=7Hz), 1.62-1.75(2H, m), 2.45(3H, s), 3.46-3.56(2H, m), 4.82-4.95(1H, m),5.90(2H, s), 7.97(1H, d, J=8 Hz), 8.11-8.18(2H, m), 8.28(1H, d, J=1 Hz).MS(ESI): m/z 535(M−1). m.p. 228-230° C.

EXAMPLE 136

In the same manner as in Example 104,3-[(5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as pale-yellow crystals (101 mg) from3-[(5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (90 mg) and (E)-1-penten-1-ylsulfonamide sodium salt (57 mg).

¹H-NMR(DMSO-d₆): 0.86(3H, t, J=7 Hz), 1.24(6H, d, J=7 Hz), 1.37-1.51(2H,m), 2.20-2.30(2H, m), 2.43(3H, s), 4.84-4.95(1H, m), 5.90(2H, s),6.78(1H, d, J=8 Hz), 6.85-6.98(1H, m), 7.94(1H, d, J=8 Hz), 8.13(2H, d,J=8 Hz), 8.28(1H, d, J=1 Hz). MS(ESI): m/z 533(M−1). m.p. 242-244° C.

EXAMPLE 137

In the same manner as in Example 1,3-[(5-(N-(isopropoxy-carbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as colorless crystals (68 mg) from3-[(5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (80 mg) and (4-methylbenzene)sulfonamide (51 mg).

¹H-NMR(CDCl₃): 1.31(6H, d, J=7 Hz), 2.42(3H, s), 2.71(3H, s),4.98-5.09(1H, m), 5.64(2H, s), 7.34(2H, d, J=8 Hz), 8.00(2H, d, J=1 Hz),8.05(2H, d, J=8 Hz), 8.18(1H, d, J=1 Hz), 8.29(1H, s). MS(ESI): m/z555(M−1). m.p. 229-231° C.

EXAMPLE 138

In the same manner as in Example 1,3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-5-(1-pentanesulfonyl)carbamoyl-3H-imidazo[4,5-b]pyridinewas obtained as pale-yellow crystals (182 mg) from3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (190 mg) and 1-pentanesulfonamide (128 mg).

¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.28-1.50(4H, m), 1.83-1.95(2H, m),2.65(3H, s), 3.53-3.60(2H, m), 5.60(2H, s), 7.53(1H, s), 7.74(1H, s),8.16(1H, d, J=8 Hz), 8.25(1H, d, J=8 Hz). MS(ESI): m/z 468(M−1). m.p.161-163° C.

EXAMPLE 139

In the same manner as in Example 1,3-((2,4-dichloro-pyridin-5-yl)methyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinewas obtained as pale-yellow crystals (195 mg) from3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (180 mg) and (4-methylbenzene)sulfonamide (137 mg).

¹H-NMR(DMSO-d₆): 2.39(3H, s), 2.56(3H, s), 5.83(2H, s), 7.45(2H, d, J=8Hz), 7.86(1H, d, J=8 Hz), 7.91(1H, s), 7.94(2H, s), 8.11(1H, d, J=8 Hz),8.23(1H, s). MS(ESI): m/z 488(M−1). m.p. 248-250° C.

EXAMPLE 140

In the same manner as in Example 85,3-(2-chloro-4-(phenylethynyl)benzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinesodium salt was obtained as colorless crystals (133 mg) from3-(2-chloro-4-(phenylethynyl)-benzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(172 mg).

m.p. 175-178° C. ¹H-NMR(DMSO-d₆): 0.83(3H, t, J=8 Hz), 1.18-1.46(4H, m),1.50-1.64(2H, m), 2.46(3H, s), 2.58(3H, s), 2.99-3.09(2H, m), 5.59(2H,s), 6.45(1H, d, J=8 Hz), 7.35-7.46(4H, m), 7.51-7.60(2H, m), 7.78(1H, d,J=1 Hz), 7.85(1H, s). MASS(ESI): m/z 547(M−Na−1).

EXAMPLE 141

In the same manner as in Example 85,3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinesodium salt was obtained as colorless crystals (78 mg) from3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(77 mg).

m.p.: >250° C. ¹H-NMR(DMSO-d₆): 0.82(3H, t, J=8 Hz), 1.27-1.36(4H, m),1.50-1.65(2H, m), 2.48(3H, s), 2.99-3.09(2H, m), 5.59(2H, s), 6.50(1H,d, J=8 Hz), 7.17(1H, d, J=4 Hz), 7.43(1H, dd, J=8, 1 Hz), 7.47(1H, d,J=4 Hz), 7.86(1H, d, J=8 Hz), 7.94(1H, d, J=8 Hz), 7.99(1H, d, J=8 Hz).MASS(ESI): m/z 549(M−Na−1).

EXAMPLE 142

In the same manner as in Example 85,3-(2-chloro-4-(phenylethynyl)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinesodium salt was obtained as colorless crystals (77 mg) from3-(2-chloro-4-(phenylethynyl)-benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine(85 mg).

m.p. >250° C. ¹H-NMR(DMSO-d₆): 2.30-2.44(3H, s), 2.57(3H, s), 5.55(2H,s), 6.41(1H, d, J=8 Hz), 7.15(2H, d, J=8 Hz), 7.36(1H, dd, J=8, 1 Hz),7.39-7.47(3H, m), 7.51-7.60(2H, m), 7.70(2H, d, J=8 Hz), 7.77(1H, d, J=1Hz), 7.84(1H, s). MASS(ESI): m/z 567(M−Na−1).

EXAMPLE 143

In the same manner as in Example 85,5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridinesodium salt was obtained as colorless crystals (105 mg) from5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine(134 mg).

m.p. >250° C. ¹H-NMR(DMSO-d₆): 2.49(3H, s), 2.58(3H, s), 5.59(2H, s),6.47(1H, d, J=8 Hz), 7.08(1H, d, J=4 Hz), 7.27(1H, d, J=4 Hz),7.34-7.54(4H, m), 7.65(2H, d, J=8 Hz), 7.82-7.86(2H, m). MASS(ESI): m/z615(M−Na−1).

EXAMPLE 144

3-[2-Chloro-4-(1-pentyloxy)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine(200 mg) was dissolved in N,N-dimethylformamide (1.5 ml) at 80° C. and1N sodium hydroxide (0.7 ml) was added dropwise at the same temperature,which was followed by stirring at room temperature for 1.5 hr. Theprecipitated crystals were collected by filtration and washed with amixed solvent (1.5 ml) of N,N-dimethylformamide:water=2:1 and water (0.5ml) to give3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinesodium salt (199 mg) as colorless crystals.

m.p.: 308-310° C. ¹H-NMR(DMSO-d₆): 0.88(3H, t, J=6 Hz), 1.20-1.42(4H,m), 1.67(2H, m), 2.30(3H, s), 2.42(3H, s), 3.92(2H, t, J=6 Hz), 5.46(2H,s), 6.43(1H, d, J=8 Hz), 6.80(1H, dd, J=8, 2 Hz), 7.10(1H, d, J=2 Hz),7.18(2H, d, J=8 Hz), 7.74(2H, d, J=8 Hz), 7.90(1H, d, J=8 Hz), 8.00(1H,d, J=8 Hz).

EXAMPLE 145

In the same manner as in Example 1,3-(4-(N-(ethoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(210 mg) was obtained as a white powder from3-(4-(N-(ethoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (177 mg).

m.p.: 149-150° C. ¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.26(3H, t, J=7Hz), 1.24-1.52(4H, m), 1.78-2.02(2H, m), 2.65(3H, s), 3.30(3H, s),3.44-3.66(2H, m), 4.19(2H, q, J=7 Hz), 5.56(2H, s), 6.66(1H, d, J=8 Hz),7.11(1H, dd, J=8 and 2 Hz), 7.46(1H, d, J=2 Hz), 8.13(1H, d, J=8 Hz),8.21(1H, d, J=8 Hz), 9.85(1H, br.s). MASS(APCI): m/e 536(M+H)⁺.

EXAMPLE 146

In the same manner as in Example 1,3-(4-(N-(benzyloxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(107 mg) was obtained as a white powder from3-(4-(N-(benzyloxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (102 mg).

m.p.: 120-121° C. ¹H-NMR(CDCl₃): 0.89(3H, t, J=7 Hz), 1.18-1.55(4H, m),1.78-2.02(2H, m), 2.63(3H, s), 3.32(3H, s), 3.45-3.65(2H, m), 5.17(2H,m), 5.56(2H, s), 6.66(1H, d, J=8 Hz), 7.12(1H, dd, J=8 and 2 Hz),7.22-7.44(5H, m), 7.47(1H, d, J=2 Hz), 8.13(1H, d, J=8 Hz), 8.21(1H, d,J=8 Hz), 9.83(1H, br.s). MASS(APCI): m/e 598(M+H)⁺.

INDUSTRIAL APPLICABILITY

The above-mentioned sulfonamide compounds and pharmaceuticallyacceptable salts thereof of the present invention are useful aspharmaceutical preparations which, based on the hypoglycemic action, areused for the prophylaxis and treatment of, for example, impaired glucosetolerance disorder, diabetes (e.g., type II diabetes), gestationaldiabetes, diabetic complications (e.g., diabetic gangrene, diabeticarthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabeticnephropathy, diabetic dermatopathy, diabetic neuropathy, diabeticcataract, diabetic retinopathy and the like), insulin resistancesyndrome (e.g., insulin receptor abnormality, Rabson-Mendenhallsyndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome,Lawrence syndrome, Cushing syndrome, acromegaly and the like),polycystic ovary syndrome, hyperlipidemia, atherosclerosis,cardiovascular diseases (e.g., stenocardia, cardiac failure and thelike), hyperglycemia (e.g., those characterized by abnormalsaccharometabolism such as eating disorders), pancreatitis,osteoporosis, hyperuricemia, hypertension, inflammatory bowel diseases,skin disorders related to an anomaly of differentiation of epidermiccells; and which, based on the cGMP-PDE (particularly PDE-V) inhibitoryaction, smooth muscle relaxing action, bronchodilating action,vasodilating action, smooth muscle cell inhibitory action, allergysuppressing action and the like, are used for angina pectoris, pulmonaryhypertension, congestive heart failure, glomerulopathy (e.g., diabeticglomerulosclerosis), tubulointerstitial disorders (e.g., kidney diseasesinduced by FK506, cyclosporine and the like), renal failure,angiostenosis (e.g., after percutaneous arterioplasty), peripheralvascular diseases, cerebral apoplexy, chronic reversible obstructiveimpairment (e.g., bronchitis, asthma inclusive of chronic asthma andallergic asthma), autoimmune diseases, allergic rhinitis, urticaria,glaucoma, diseases characterized by impaired intestinal motility (e.g.,irritable bowel syndrome), impotence (e.g., organic impotence, psychicimpotence and the like), nephritis, cancer cachexia, restenosis afterPTCA, cachexia (e.g., progressive weight loss due to lipolysis,myolysis, anemia, edema, anorexia and the like in chronic diseases suchas cancer, tuberculosis, endocrine diseases and AIDS, and the like. Acombination of a compound of formula (I) or pharmaceutically acceptablesalts thereof and a retinoid is useful for treating disease statescaused by uncontrolled cell proliferation, including cancer, restenosisand atherosclerosis.

This application is based on application Nos. 259283/1999, 367540/1998and 346175/1998 filed in Japan on Aug. 9, 1999, Dec. 24, 1998 and Dec.4, 1998, respectively, the contents of which are incorporated hereintoby reference.

1. A sulfonamide compound of formula (I):

wherein R¹ is an aryl or an group unsaturated 5- or 6-memberedheteromonocyclic group having 1 to 4 nitrogen atom(s), which issubstituted by at least one substituent selected from the groupconsisting of: (1) aryl, (2) pyrrolyl, pyrrolidinyl, oxazolidinyl,thienyl, or furanyl, each of which may be optionally substituted by oxoor halogen, (3) halogen, (4) halo(lower)alkyl, (5) lower alkoxyoptionally substituted by cyclo(lower)alkyl, (6) amino optionallysubstituted by at least one substituent selected from the groupconsisting of lower alkyl optionally substituted by cyclo(lower)alkyl,protected carboxy, acyl, lower alkylcarbamoyl, and lower alkanesulfonyl,(7) nitro and (8) lower alkynyl optionally substituted by aryl; R² is alower alkyl or lower alkoxy; R³ is a hydrogen or lower alkyl; R⁴ is: alower alkenyl optionally substituted by aryl or unsaturated 5- or6-membered heteromonocyclic group having 1 to 4 nitrogen atom(s), aryloptionally substituted by carboxy or protected carboxy, lower alkyloptionally substituted by acyloxy, amino optionally substituted by loweralkyl, or unsaturated 5- or 6-membered heteromonocyclic group having onesulfur atom or one oxygen atom optionally substituted by halogen; and Ais a lower alkylene; or a salt, solvate, or hydrate of a compound offormula (I), with the proviso that A is not methylene and R¹ is not:

 wherein X is halogen, Y is C or N, and R⁵ is pyrrolyl, furyl, or aminosubstituted by protected carboxy and optionally substituted by loweralkyl.
 2. The compound of claim 1, wherein R¹ is a substituted arylgroup.
 3. The compound of claim 1, wherein R¹ is a substitutedunsaturated 5- or 6-membered heteromonocyclic group having 1 to 4nitrogen atom(s).
 4. The sulfonamide compound of claim 1, wherein R⁴ is:lower alkenyl substituted by an unsaturated 5- or 6-memberedheteromonocyclic group having 1 to 4 nitrogen atom(s), aryl substitutedby carboxy or protected carboxy, lower alkyl substituted by acyloxy, oramino optionally substituted by lower alkyl; or a salt, solvate, orhydrate thereof.
 5. The sulfonamide compound of claim 1, wherein R¹ ispyridyl substituted by at least one substituent selected from the groupconsisting of: (1) aryl, (2) pyrrolyl, pyrrolidinyl, oxazolidinyl,thienyl, or furanyl, each of which may be optionally substituted by oxoor halogen, (3) halogen, (4) halo(lower)alkyl, (5) lower alkoxyoptionally substituted by cyclo(lower)alkyl, (6) amino optionallysubstituted by at least one substituent selected from the groupconsisting of lower alkyl optionally substituted by cyclo(lower)alkyl,protected carboxy, acyl and lower alkanesulfonyl, (7) nitro and (8)lower alkynyl optionally substituted by aryl; or a salt, solvate, orhydrate thereof.
 6. The sulfonamide compound of claim 1, wherein A ismethylene.
 7. The sulfonamide compound of claim 1, wherein R² is methyl,ethyl or ethoxy.
 8. The sulfonamide compound of claim 1, wherein R³ ishydrogen or methyl.
 9. The sulfonamide compound of claim 1, wherein R⁴is (E)-2-(4-pyridyl)vinyl, 1-pentyl, 1-butyl, 4-methylphenyl,1-propylamino, 1-butylamino, (E)-2-(phenyl)vinyl, 5-bromo-2-thienyl,5-chloro-2-thienyl, 4-ethoxycarbonylphenyl, 4-carboxyphenyl, or4-acetoxybutyl.
 10. The sulfonamide compound of claim 1, which is:3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(E)-[2-(4-pyridyl)ethene]sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,5-[(4-acetoxybutane)sulfonylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(4-ethoxycarbonylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(4-carboxybenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-methoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-methoxybenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-ethoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-ethoxybenzyl)-2-methyl-5-((1-propylaminosulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine,5-((1-butylaminosulfonyl)carbamoyl)-3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(1-propoxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-propoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-isopropoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-isopropoxybenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-5-((E)-(2-phenylethene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine,3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-5-[(5-chlorothiophen-2-yl)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,5-((1-propylaminosulfonyl)carbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,5-((1-butylaminosulfonyl)carbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-((cyclopentylmethyl)oxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4((cyclopentylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-ethoxybenzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-ethoxybenzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,5-(1-butanesulfonylcarbamoyl)-3-[2-chloro-4-(1-propoxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,5-(1-butanesulfonylcarbamoyl)-3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine,3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(ethylmethylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(methyl-(1-propyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(4-((1-butyl)methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(dimethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(ethylmethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(methyl-(1-propyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-((1-butyl)methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(methyl-(1-pentyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl)-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(ethylmethylamino)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-[(3-chloro-5-trifluoromethyl)-2-pyridyl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-phenylbenzyl)-2-ethoxy-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(1-propylaminosulfonyl)carbamoyl]-3H-imidazo[4,5-b]pyridine,3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3-H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(methyl(pivaloyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine,5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(ethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(N,N-diethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(N-ethyl-N-(1-pentyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(methylamino)benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(N-methyl-N-propylamino)benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-[2-chloro-4-(cyclohexylmethyloxy)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinesodium salt,3-(2,4-dichloro-5-nitrobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2,4-dichloro-5-nitrobenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-[2,4-dichloro-5-(N,N-dimethylamino)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-[2,4-dichloro-5-(N,N-dimethylamino)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(4-(N-(1-butanesulfonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(N-valerylamino)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(4-(N-(1-butanesulfonyl)amino)-2-chlorobenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(N-(t-butylacetyl)amino)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(4-amino-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(4-amino-2-chlorobenzyl)-5-(1-butanesulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(4-amino-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(3-(1-propyl)ureido)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-(4-(1-methyl-3-(1-propyl)ureido)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(2-oxo-1-pyrrolidinyl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(((2-(4-methylbenzene)sulfonylcarbamoyloxy)-ethyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine,3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-((6-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-5-((4-methylbenzenesulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine,3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-5-(((E)-2-phenylethenesulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine,3-[(2-chloro-6-phenylpyridin-3-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-[(2-chloro-6-phenylpyridin-3-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,3-(2-chloro-4-(phenylethynyl)benzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinesodium salt,3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridinesodium salt,3-(2-chloro-4-(phenylethynyl)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinesodium salt,5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridinesodium salt, or3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinesodium salt; or a salt, solvate, or hydrate thereof.
 11. The sulfonamidecompound of claim 1, which is:3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-[(2-chloro-6-phenylpyridin-3-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine,3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine,or3-(2-chloro-4-(phenylethynyl)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridinesodium salt; or a salt, solvate, or hydrate thereof.
 12. The sulfonamidecompound of claim 1 that is an alkali metal salt.
 13. The sulfonamidecompound of claim 1 that is an alkaline earth metal salt.
 14. Thesulfonamide compound claim 1 that is an inorganic base salt.
 15. Thesulfonamide compound of claim 1 that is an ammonium salt.
 16. Thesulfonamide compound of claim 1 that is an organic amine salt.
 17. Thesulfonamide compound of claim 1 that is an inorganic acid salt.
 18. Thesulfonamide compound of claim 1 that is an organic acid salt.
 19. Thesulfonamide compound of claim 1 that is an organic carboxylic acid salt.20. The sulfonamide compound of claim 1 that is a sulfonic acid salt.21. The sulfonamide compound of claim 1 that is an amino acid salt. 22.The sulfonamide compound of claim 1 that is a solvate.
 23. Thesulfonamide compound of claim 1 that is a hydrate.
 24. The sulfonamidecompound of claim 1 that is an ethanol solvate.
 25. A compositioncomprising the sulfonamide compound of claim 1 or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof.
 26. A pharmaceuticalpreparation or therapeutic agent comprising the sulfonamide compound ofclaim 1 and a pharmaceutically acceptable excipient or carrier.
 27. Thepharmaceutical preparation or therapeutic agent of claim 26 thatcomprises one or more adjuvant(s), auxiliary substance(s),stabilizer(s), moistening agent(s), emulsifier(s), or bufferingagent(s).
 28. The pharmaceutical preparation or therapeutic agent ofclaim 26 in the form of a capsule, tablet, sugar-coated tablet, orgranule.
 29. The pharmaceutical preparation or therapeutic agent ofclaim 26 in the form of a suppository, gel or ointment.
 30. Thepharmaceutical preparation or therapeutic agent of claim 26 in the formof a liquid.
 31. The pharmaceutical preparation or therapeutic agent ofclaim 26 in the form of a suspension, emulsion or lotion.
 32. Thepharmaceutical preparation or therapeutic agent of claim 26 in a unitdose ranging from about 0.1 mg to about 1000 mg.
 33. A method for makingthe pharmaceutical preparation or therapeutic agent of claim 26comprising admixing said sulfonamide compound or a salt or solvatethereof, with a pharmaceutically acceptable excipient or carrier.
 34. Amethod for the treatment of a disease or disorder selected from thegroup consisting of diabetes and gestational diabetes comprisingadministering to a mammal in need thereof an effective amount of thesulfonamide compound of claim 1 or a salt, solvate, or hydrate thereof.35. The method of claim 34 comprising administering to said mammal adaily dose of said sulfonamide compound ranging from 0.1 to 1000 mg. 36.A method for reducing blood sugar level in a mammal comprisingadministering to said mammal an therapeutically effective amount of thesulfonamide compound of claim 1 or a salt, solvate or hydrate thereof.37. The method of claim 36 that comprises treating a human in need of areduced blood sugar level.
 38. The method of claim 36 that comprisesadministering a daily dose of said sulfonamide compound to said mammalranging from about 0.1 mg to about 1000 mg.
 39. A method for producingthe sulfonamide compound of formula (I) of claim 1 or a salt, solvate orhydrate thereof, comprising: reacting a compound of formula (II):

wherein R¹ an aryl or an unsaturated 5- or 6-membered heteromonocyclicgroup having 1 to 4 nitrogen atom(s), substituted by at least onesubstituent selected from the group consisting of (1) unsubstitutedaryl, (2) pyrrolyl, pyrrolidinyl, oxazolidinyl, thienyl, or furanyl,each of which may be optionally substituted by oxo or halogen, (3)halogen, (4) halo(lower)alkyl, (5) lower alkoxy optionally substitutedby cyclo(lower)alkyl, (6) amino optionally substituted by at least onesubstituent selected from the group consisting of lower alkyl optionallysubstituted by cyclo(lower)alkyl, protected carboxy, acyl, loweralkylcarbamoyl, and lower alkanesulfonyl, (7) nitro and (8) loweralkynyl optionally substituted by aryl, R² is a lower alkyl or loweralkoxy, R³ is hydrogen or lower alkyl, and A is a lower alkylene,  orreactive derivative at the carboxy thereof or a salt thereof,  with acompound of formula (III):R⁴—SO₂NH₂  (III)  wherein R⁴ is a lower alkenyl optionally substitutedby aryl or an unsaturated 5- or 6-membered heteromonocyclic group having1 to 4 nitrogen atom(s), aryl optionally substituted by carboxy orprotected carboxy, lower alkyl optionally substituted by acyloxy, aminooptionally substituted by lower alkyl, or unsaturated 5- or 6-memberedheteromonocyclic group having one sulfur atom or one oxygen atomoptionally substituted by halogen,  with the proviso that A is notmethylene and R¹ is not:

 wherein X is halogen, Y is C or N, and R⁵ is pyrrolyl, furyl, or aminosubstituted by protected carboxy and optionally substituted by loweralkyl.